Substituted tricyclic compounds as FGFR inhibitors

ABSTRACT

The present invention relates to tricyclic compounds, and pharmaceutical compositions of the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.

FIELD OF THE INVENTION

The present invention relates to tricyclic compounds, and pharmaceuticalcompositions including the same, that are inhibitors of one or more FGFRenzymes and are useful in the treatment of FGFR-associated diseases suchas cancer.

BACKGROUND OF THE INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

Aberrant activation of this pathway either through overexpression of FGFligands or FGFR or activating mutations in the FGFRs can lead to tumordevelopment, progression, and resistance to conventional cancertherapies. In human cancer, genetic alterations including geneamplification, chromosomal translocations and somatic mutations thatlead to ligand-independent receptor activation have been described.Large scale DNA sequencing of thousands of tumor samples has revealedthat components of the FGFR pathway are among the most frequentlymutated in human cancer. Many of these activating mutations areidentical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore,development of inhibitors targeting FGFR may be useful in the clinicaltreatment of diseases that have elevated FGF or FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer and other diseases, and the FGFR inhibitorsdescribed herein help address this need.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined hereinbelow.

The present invention is further directed to a compound of Formula II,III, or IV:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined hereinbelow.

The present invention is further directed to a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined hereinbelow.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of any one of Formulas I, II, III, IV,and V, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of treating cancerin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound of any one of Formulas I, II, III, IV,and V, or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a method of treating amyeoloproliferative disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of any one ofFormulas I, II, III, IV, and V, or a pharmaceutically acceptable saltthereof.

The present invention is further directed to a method of treating askeletal or chondrocyte disorder in a patient comprising administeringto the patient a therapeutically effective amount of a compound of anyone of Formulas I, II, III, IV, and V, or a pharmaceutically acceptablesalt thereof.

DETAILED DESCRIPTION

The present invention is related to an FGFR inhibitor which is acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is NR⁹, O, or CR¹⁷R¹⁸;

ring A is:

X is CR¹⁵ or N;

Y is NR¹⁶, O, or S;

Z is N or CH;

Q is absent, O, NR^(16a), or CR^(12a)R^(13a);

n is 0 or 1, wherein when n is 0 then Q is not absent;

R¹ is H, NR^(A)R^(B), halo, and C₁₋₃ alkyl;

-   R² and R³ are each independently selected from H, CN,    C(O)NR^(c)R^(d), and C₁₋₇ alkyl, wherein said C₁₋₇ alkyl is    optionally substituted by 1, 2, or 3 substituents independently    selected from halo, OR^(a), CN, NR^(c)R^(d), and C(O)NR^(c)R^(d);-   or R² and R³ together with the carbon atom to which they are    attached form a 3-7 membered cycloalkyl ring or a 4-7 membered    heterocycloalkyl ring, each optionally substituted by 1, 2, or 3    substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),    C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),    NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a);

R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(9a);

each R^(9a) is independently selected from Cy¹, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R¹⁰, R¹¹, R¹², R¹³, R^(12a), R^(13a), R¹⁴, R¹⁵, R¹⁷, and R¹⁸ are eachindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(10a);

each R^(10a) is independently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

or R¹² and R¹³ together with the carbon atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-,or 7-membered heterocycloalkyl group, each optionally substituted with1, 2, or 3 substituents independently selected from Cy², C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

or R^(12a) and R^(13a) together with the carbon atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-,5-, 6-, or 7-membered heterocycloalkyl group, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

or R¹⁷ and R¹⁸ together with the carbon atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-,or 7-membered heterocycloalkyl group, each optionally substituted with1, 2, or 3 substituents independently selected from Cy², C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R¹⁶ and R^(16a) are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, aryl-C₁₋₄ alkyl,cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, aryl-C₁₋₄ alkyl,cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy³,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

R^(A) and R^(B) are each independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

Cy¹, Cy², and Cy³ are each independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 3-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4),R^(c4), and R^(d4), R^(a5), R^(b5), R^(c5), and R^(d5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl is optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, CN, OR^(a6), SR^(b6), S(O)₂R^(b6),C(O)R^(b6), S(O)₂NR^(c6)R^(d6), and C(O)NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; and

each R^(e6) is independently selected from H, C₁₋₄ alkyl, and CN;

provided that when ring A is

W is NR⁹;

R¹, R², R³ are each H; and

R⁹ is C₁₋₆ alkyl;

then at least four of R⁴, R⁵, R⁶, R⁷, and R⁸ are other than H.

In some embodiments, the present invention is related to an FGFRinhibitor which is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is NR⁹ or O;

ring A is:

X is CR¹⁵ or N;

Y is NR¹⁶, O, or S;

Z is N or CH;

Q is absent, O, NR^(16a), or CR^(12a)R^(13a);

n is 0 or 1, wherein when n is 0 then Q is not absent;

R¹ is H, NR^(A)R^(B), halo, and C₁₋₃ alkyl;

R² and R³ are each independently selected from H, CN, C(O)NR^(c)R^(d),and C₁₋₇ alkyl, wherein said C₁₋₇ alkyl is optionally substituted by 1,2, or 3 substituents independently selected from halo, OR^(a), CN,NR^(c)R^(d), and C(O)NR^(c)R^(d);

or R² and R³ together with the carbon atom to which they are attachedform a 3-7 membered cycloalkyl ring or a 4-7 membered heterocycloalkylring, each optionally substituted by 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a);

R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 memberedheterocycloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and3-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (3-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (3-10 membered heterocycloalkyl)-C₁₋₄ alkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(9a);

each R^(9a) is independently selected from Cy¹, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R¹⁰, R¹¹, R¹², R¹³, R^(12a), R^(13a), R¹⁴ and R¹⁵ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and3-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a);

each R^(10a) is independently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

or R¹² and R¹³ together with the carbon atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-,or 7-membered heterocycloalkyl group, each optionally substituted with1, 2, or 3 substituents independently selected from Cy², C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

or R^(12a) and R^(13a) together with the carbon atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-,5-, 6-, or 7-membered heterocycloalkyl group, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R¹⁶ and R^(16a) are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 3-10 membered heterocycloalkyl, aryl-C₁₋₄ alkyl,cycloalkyl-C₁₋₄ alkyl, heteroaryl-C₁₋₄ alkyl, and heterocycloalkyl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (3-10 memberedheterocycloalkyl)-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from Cy³, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

R^(A) and R^(B) are each independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (3-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (3-10 membered heterocycloalkyl)-C₁₋₄ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

Cy¹, Cy², and Cy³ are each independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 3-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4),R^(c4), and R^(d4), R^(a5), R^(b5), R^(c5), and R^(d5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (3-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,3-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (3-10membered heterocycloalkyl)-C₁₋₄ alkyl is optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)²R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6); each R^(e1), R^(e2),R^(e3), R^(e4), and R^(e5) is independently selected from H, C₁₋₄ alkyl,CN, OR^(a6), SR^(b6), S(O)₂R^(b6), C(O)R^(b6), S(O)₂NR^(c6)R^(d6), andC(O)NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; and each R^(e6) is independently selected from H, C₁₋₄alkyl, and CN;

provided that when ring A is

W is NR⁹;

R¹, R², R³ are each H; and

R⁹ is C₁₋₆ alkyl;

then at least four of R⁴, R⁵, R⁶, R⁷, and R⁸ are other than H.

In some embodiments:

R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(9a);

each R^(9a) is independently selected from Cy¹, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R¹⁰, R¹¹, R¹², R¹³, R^(12a), R^(13a), R¹⁴ and R¹⁵ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a);

each R^(10a) is independently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

or R¹² and R¹³ together with the carbon atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-,or 7-membered heterocycloalkyl group, each optionally substituted with1, 2, or 3 substituents independently selected from Cy², C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

or R^(12a) and R^(13a) together with the carbon atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-,5-, 6-, or 7-membered heterocycloalkyl group, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R¹⁶ and R^(16a) are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy³,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

R^(A) and R^(B) are each independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

Cy¹, Cy², and Cy³ are each independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4),R^(c4), and R^(d4), R^(a5), R^(b5), R^(c5), and R^(d5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl is optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6); each R^(e1), R^(e2),R^(e3), R^(e4), and R^(e5) is independently selected from H, C₁₋₄ alkyl,CN, OR^(a6), SR^(b6), S(O)₂R^(b6), C(O)R^(b6), S(O)₂NR^(c6)R^(d6), andC(O)NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; and each R^(e6) is independently selected from H, C₁₋₄alkyl, and CN.

In some embodiments, W is NR⁹ or O.

In some embodiments, W is O.

In some embodiments, W is NR⁹ or CR¹⁷CR¹⁸

In some embodiments, W is CR¹⁷CR¹⁸.

In some embodiments, W is NR⁹.

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from R^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, or 3 R^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith R^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, or (5-10 memberedheteroaryl)-C₁₋₄ alkyl, each optionally substituted with 1, 2, or 3substituents independently selected from R^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀aryl-C₁₋₄ alkyl, or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 3-10membered heterocycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, or C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, each optionally substituted with 1, 2, or 3substituents independently selected from R^(9a).

In some embodiments, R⁹ is H, C₁₋₆ alkyl optionally substituted by OH,C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl.

In some embodiments, R⁹ is H, C₁₋₆ alkyl optionally substituted by OH,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl.

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 3-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, or C₃₋₁₀cycloalkyl-C₁₋₄ alkyl.

In some embodiments, R⁹ is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, or C₃₋₁₀cycloalkyl-C₁₋₄ alkyl.

In some embodiments, R⁹ is C₁₋₆ alkyl.

In some embodiments, R⁹ is methyl.

In some embodiments, R⁹ is phenyl optionally substituted with 1, 2, or 3substituents independently selected from R^(9a).

In some embodiments, R⁹ is 5-10 membered heteroaryl optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(9a).

In some embodiments, R⁹ is pyridyl optionally substituted with 1, 2, or3 substituents independently selected from R^(9a).

In some embodiments, R⁹ is pyridyl.

In some embodiments, R¹⁷ and R¹⁸ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments, R¹⁷ and R¹⁸ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, and CN, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments, R¹⁷ and R¹⁸ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom R^(10a).

In some embodiments, R¹⁷ and R¹⁸ are each independently selected from Hand C₁₋₆ alkyl.

In some embodiments, R¹⁷ is H.

In some embodiments, R¹⁸ is H.

In some embodiments, R¹⁷ and R¹⁸ are both H.

In some embodiments, R¹⁷ and R¹⁸ are both C₁₋₆ alkyl.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form C₃₋₇ cycloalkyl.

In some embodiments, R² and R³ are each independently selected from H,CN, C(O)NR^(c)R^(d), and C₁₋₇ alkyl, wherein said C₁₋₇ alkyl isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, OR^(a), CN, NR^(c)R^(d), and C(O)NR^(c)R^(d).

In some embodiments, R² and R³ are each H.

In some embodiments, each of R¹, R², and R³ is H.

In some embodiments, each of R¹, R², R³, R¹², and R¹³ is H.

In some embodiments, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

In some embodiments, at least one of R⁴, R⁵, R⁶, R⁷, and R⁸ is otherthan H.

In some embodiments, at least two of R⁴, R⁵, R⁶, R⁷, and R⁸ is otherthan H.

In some embodiments, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a1).

In some embodiments, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyselected from H, halo, and methoxy.

In some embodiments, R⁵ and R⁷ are both methoxy and R⁴, R⁶, and R⁸ areeach independently selected from H and halo.

In some embodiments, R⁴ is halo, R⁵ is methoxy, R⁶ is H, R⁷ is methoxy,and R⁸ is halo.

In some embodiments, R¹⁰, R¹¹, R¹², R¹³, R^(12a), R^(13a), R¹⁴, and R¹⁵,are each independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(10a);

In some embodiments, R¹² and R¹³ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 memberedheterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and3-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments, R¹² and R¹³ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments, R¹² and R¹³ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3). In some embodiments, R¹² and R¹³ together with thecarbon atom to which they are attached form a 3-, 4-, 5-, 6-, or7-membered cycloalkyl group.

In some embodiments, the compound has Formula II, III, or IV:

In some embodiments, the compound has Formula II.

In some embodiments where the compound has Formula II, W is NR⁹ orCR¹⁷R¹⁸.

In some embodiments where the compound has Formula II, W is NR⁹.

In some embodiments where the compound has Formula II, W is CR¹⁷R¹⁸.

In some embodiments where the compound has Formula II, X is CR¹⁵.

In some embodiments where the compound has Formula II, X is CH.

In some embodiments, R¹⁵ is H or 5-10 membered heteroaryl optionallysubstituted by C₁₋₆ alkyl.

In some embodiments, R¹⁰ is H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, orC(O)NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy², halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R¹⁰ is H, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, CN, orC(O)NR^(c3)R^(d3), wherein said C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments where the compound has Formula II, R¹⁰ is H, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 memberedheterocycloalkyl, CN, or C(O)NR^(c3)R^(d3), wherein said C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 3-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(10a).

In some embodiments where the compound has Formula II, R¹⁰ is H, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, or C(O)NR^(c3)R^(d3), wherein said C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(10a).

In some embodiments where the compound has Formula II, R¹⁰ is H, methyl,ethyl, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, orC(O)NR^(c3)R^(d3), wherein said methyl, ethyl, phenyl, pyrazolyl,piperidinyl, and tetrahydropyridinyl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy²,NR^(c3)R^(d3), and C₁₋₆ alkyl optionally substituted with OR^(a3).

In some embodiments where the compound has Formula II, R¹⁰ is H, phenyl,pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR^(c3)R^(d3),wherein said phenyl, pyrazolyl, piperidinyl, and tetrahydropyridinyl areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from Cy² and C₁₋₆ alkyl optionally substituted with OR^(a3).

In some embodiments where the compound has Formula II, R¹⁰ is H,(4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl,1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano,1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl,dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl,(3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl,cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl,(3-hydroxypiperidin-1-yl)carbonyl, tetrahydro-2H-pyran-4-yl,(4-methylpiperazin-1-yl)carbonyl, morpholin-4-ylcarbonyl, or(4,4-difluoropiperidin-1-yl)carbonyl.

In some embodiments where the compound has Formula II, R¹⁰ is H,(4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl,1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano,1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl,dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl,(3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl,cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl, or(3-hydroxypiperidin-1-yl)carbonyl.

In some embodiments where the compound has Formula II, R¹⁰ is H,(4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl,1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano,1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl,dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl,(3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl,cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl,(3-hydroxypiperidin-1-yl)carbonyl, morpholin-4-ylmethyl,(4-methylpiperazin-1-yl)methyl, 4-ethylpiperazin-1-yl)methyl,4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl,cyanopiperidinylmethyl, cyanopyrrolidinylmethyl,(1-methylpiperidin-4-yl)aminomethyl, (tetrahydrofuran-3-ylamino)methyl,1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl,(1-methyl-1H-pyrazol-4-yl)methyl, 2-pyridin-2-ylethyl,2-morpholin-4-ylethyl, 2-(diethylamino)ethyl,2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl,(4-ethylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl]methyl,2-(4-ethylpiperazin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl,(pyridin-3-yloxy)methyl, (2-oxopyridin-1(2H)-yl)methyl,(3-cyanoazetidin-1-yl)methyl, (3-fluoroazetidin-1-yl)methyl, or(3-hydroxyazetidin-1-yl)methyl.

In some embodiments where the compound has Formula II, R¹⁰ ismorpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl,4-ethylpiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl,4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl,cyanopiperidinylmethyl, cyanopyrrolidinylmethyl,(1-methylpiperidin-4-yl)aminomethyl, (tetrahydrofuran-3-ylamino)methyl,1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl,(1-methyl-1H-pyrazol-4-yl)methyl, 2-pyridin-2-ylethyl,2-morpholin-4-ylethyl, 2-(diethylamino)ethyl,2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl,(4-ethylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl]methyl,or 2-(4-ethylpiperazin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl.

In some embodiments where the compound has Formula II, R¹⁰ ismorpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl,4-ethylpiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl,4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl,cyanopiperidinylmethyl, cyanopyrrolidinylmethyl, 1H-imidazol-1-ylmethyl,1H-pyrazol-1-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl,(4-ethylpiperazin-1-yl)methyl, or3-(dimethylamino)pyrrolidin-1-yl]methyl.

In some embodiments where the compound has Formula II, R¹⁰ is2-pyridin-2-ylethyl, 2-morpholin-4-ylethyl, 2-(diethylamino)ethyl,2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl,2-(4-ethylpiperazin-1-yl)ethyl, or 2-(4-methylpiperazin-1-yl)ethyl.

In some embodiments R¹⁰ is C₁₋₆ alkyl optionally substituted with 1, 2,or 3 substituents independently selected from Cy², NR^(c3)R^(d3), andC₁₋₆ alkyl optionally substituted with OR^(a3).

In some embodiments R¹⁰ is C₁₋₆ alkyl optionally substituted with 4-7membered heterocycloalkyl wherein said 4-7 membered heterocycloalkyl isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), NR^(c5)R^(d5), andNR^(c5)C(O)R^(b5).

In some embodiments where the compound has Formula II, R¹⁰ is C₁₋₆ alkyloptionally substituted with 4-7 membered heterocycloalkyl wherein said4-7 membered heterocycloalkyl is selected from morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, andwherein said 4-7 membered heterocycloalkyl is optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, CN, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), NR^(c5)R^(d5), and NR^(c5)C(O)R^(b5).

In some embodiments R^(c3) and R^(d3) together with the N atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a6), andNR^(c6)R^(d6).

In some embodiments Cy² is selected from 4-7 membered heterocycloalkyloptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5).

In some embodiments where the compound has Formula II, R¹⁰ is H.

In some embodiments where the compound has Formula II, R¹⁰ is other thanH.

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(10a).

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, and CN, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from R^(10a).

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(10a).

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areboth C₁₋₆ alkyl.

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areboth methyl.

In some embodiments where the compound has Formula II, R¹⁷ and R¹⁸ areeach independently selected from H and halo.

In some embodiments where the compound has Formula II, R¹⁷ is H.

In some embodiments where the compound has Formula II, R¹⁸ is H.

In some embodiments where the compound has Formula II, both R¹⁷ and R¹⁸are H.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl groupor a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a cyclobutyl or cyclopentyl group.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from Cy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3 substituents independently selected from Cy², halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with C₁₋₆ alkyl.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup.

In some embodiments, R¹⁷ and R¹⁸ together with the carbon atom to whichthey are attached form a tetrahydropyran ring or N-methylpiperidinering.

In some embodiments, the compound has Formula IIa:

In some embodiments, the compound has Formula IIb:

In some embodiments, the compound has Formula III.

In some embodiments where the compound has Formula III, Z is CH.

In some embodiments where the compound has Formula III, Y is S.

In some embodiments where the compound has Formula III, R¹¹ is H.

In some embodiments, the compound has Formula IIIa:

In some embodiments, the compound has Formula IIIb:

In some embodiments, the compound has Formula IV.

In some embodiments, R¹⁴ selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,and CN; wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10a).

In some embodiments where the compound has Formula IV, R¹⁴ is H, C₁₋₆alkyl, 3-10 membered heterocycloalkyl, or CN; wherein said C₁₋₆ alkyland 3-10 membered heterocycloalkyl are each optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments where the compound has Formula IV, R¹⁴ is H, C₁₋₆alkyl, 4-10 membered heterocycloalkyl, or CN; wherein said C₁₋₆ alkyland 4-10 membered heterocycloalkyl are each optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from R^(10a).

In some embodiments where the compound has Formula IV, R¹⁴ is H, methyl,1-methylpiperidinyl, CN, cyanomethyl, or 2-hydroxyethyl.

In some embodiments where the compound has Formula IV, R¹⁴ is H.

In some embodiments where the compound has Formula IV, R¹⁴ is phenyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10a).

In some embodiments, R¹⁴ is phenyl optionally substituted with R^(10a).

In some embodiments, R¹⁴ is (4-ethylpiperazin-1-yl)phenyl.

In some embodiments, the compound has Formula IVa:

In some embodiments, the compound has Formula IVb:

In some embodiments, the compound has Formula V:

In some embodiments where the compound has Formula V, W is NR⁹.

In some embodiments where the compound has Formula V, R⁹ is H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₄ alkyl, or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(9a).

In some embodiments where the compound has Formula V, R⁹ is H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl.

In some embodiments where the compound has Formula V, R⁹ is C₆₋₁₀aryl-C₁₋₄ alkyl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(9a).

In some embodiments where the compound has Formula V, R⁹ is benzyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(9a).

In some embodiments where the compound has Formula V, R⁹ is phenyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(9a).

In some embodiments where the compound has Formula V, R⁹ is H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, or C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl.

In some embodiments where the compound has Formula V, R⁹ is C₃₋₁₀cycloalkyl.

In some embodiments where the compound has Formula V, R⁹ is cyclobutyl.

In some embodiments where the compound has Formula V, R⁹ is C₁₋₆ alkyl.

In some embodiments, R⁹ is methyl, ethyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, 3-fluorophenylmethyl, or4-chloro-2-fluorophenyl.

In some embodiments where the compound has Formula V, R⁹ is methyl,ethyl, cyclopropyl, or cyclopropylmethyl.

In some embodiments where the compound has Formula V, R⁹ is methyl.

In some embodiments where the compound has Formula V, R² and R³ are eachindependently selected from H, CN, C(O)NR^(c)R^(d), and C₁₋₇ alkyl,wherein said C₁₋₇ alkyl is optionally substituted by 1, 2, or 3substituents independently selected from halo, OR^(a), CN, NR^(c)R^(d),and C(O)NR^(c)R^(d).

In some embodiments where the compound has Formula V, R² and R³ are eachH.

In some embodiments where the compound has Formula V, R², and R³ areeach H.

In some embodiments where the compound has Formula V, R¹, R², and R³ areeach H.

In some embodiments where the compound has Formula V, R⁴, R⁵, R⁶, R⁷,and R⁸ are each independently selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, and OR^(a1).

In some embodiments where the compound has Formula V, R⁴, R⁵, R⁶, R⁷,and R⁸ are each independently selected from H, halo, and methoxy.

In some embodiments where the compound has Formula V, R⁵ and R⁷ are bothmethoxy and R⁴, R⁶, and R⁸ are each independently selected from H andhalo.

In some embodiments where the compound has Formula V, R⁴ is halo, R⁵ ismethoxy, R⁶ is H, R⁷ is methoxy, and R⁸ is halo.

In some embodiments where the compound has Formula V, Q is absent.

In some embodiments where the compound has Formula V, Q is O, NR^(16a),or CR^(12a)R^(13a).

In some embodiments where the compound has Formula V, R¹² and R¹³ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 3-10 membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(10a).

In some embodiments where the compound has Formula V, R¹² and R¹³ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(10a).

In some embodiments where the compound has Formula V, R¹² and R¹³together with the carbon atom to which they are attached form a 3-, 4-,5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, each optionally substituted with 1, 2, or 3substituents independently selected from Cy², C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆alkyl is optionally substituted by 1, 2, or 3 substituents independentlyselected from Cy², halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments where the compound has Formula V, R¹² and R¹³together with the carbon atom to which they are attached form a 3-, 4-,5-, 6-, or 7-membered cycloalkyl group.

In some embodiments where the compound has Formula V, R¹² and R¹³ areeach H.

In some embodiments where the compound has Formula V, R², R³, R¹² andR¹³ are each H.

In some embodiments where the compound has Formula V, n is 1.

In some embodiments where the compound has Formula V, n is 1 and Q isabsent.

In some embodiments where the compound has Formula V, n is 0.

In some embodiments, the compound has Formula Va:

In some embodiments, the compound has Formula Vb:

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub combination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, orpyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j)”, where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl”, employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, thealkyl group is methyl, ethyl, or propyl.

As used herein, “alkenyl”, employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl”, employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. Example alkynyl groups include, but are not limited to, ethynyl,propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynylmoiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl.

As used herein, the term “haloalkyl”, employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examplehaloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and thelike.

As used herein, the term “alkoxy”, employed alone or in combination withother terms, refers to a group of formula —O-alkyl. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, “haloalkoxy”, employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Anexample haloalkoxy group is —OCF₃.

As used herein, “amino”, employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino”, employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino”, employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio”, employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl”, employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members. In some embodiments, the cycloalkyl group ismonocyclic or bicyclic. In some embodiments, the cycloalkyl group ismonocyclic. In some embodiments, the cycloalkyl group is a C₃₋₇monocyclic cycloalkyl group. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl”, employed alone or incombination with other terms, refers to a group of formulacycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the cycloalkyl portion has 3to 10 ring members or 3 to 7 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl portion is monocyclic. In some embodiments, the cycloalkylportion is a C₃₋₇ monocyclic cycloalkyl group.

As used herein, the term “heterocycloalkyl”, employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms.In some embodiments, the heterocycloalkyl group has 2 to 20 carbonatoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2heteroatoms. The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide,or a sulfonyl group (or other oxidized linkage) or a nitrogen atom canbe quaternized. In some embodiments, the heterocycloalkyl portion is aC₂₋₇ monocyclic heterocycloalkyl group. In some embodiments, theheterocycloalkyl group is a morpholine ring, pyrrolidine ring,piperazine ring, piperidine ring, tetrahydropyran ring,tetrahyropyridine, azetidine ring, or tetrahydrofuran ring.

As used herein, the term “heterocycloalkylalkyl”, employed alone or incombination with other terms, refers to a group of formulaheterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heterocycloalkyl portionhas 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members.In some embodiments, the heterocycloalkyl group is monocyclic orbicyclic. In some embodiments, the heterocycloalkyl portion ismonocyclic. In some embodiments, the heterocycloalkyl portion is a C₂₋₇monocyclic heterocycloalkyl group.

As used herein, the term “aryl”, employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl or naphthyl.

As used herein, the term “arylalkyl”, employed alone or in combinationwith other terms, refers to a group of formula aryl-alkyl-. In someembodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbonatom(s). In some embodiments, the alkyl portion is methylene. In someembodiments, the aryl portion is phenyl. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, thearylalkyl group is benzyl.

As used herein, the term “heteroaryl”, employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or 3 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl group is a monocyclic orbicyclic group having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, sulfur and oxygen. Example heteroaryl groups include, butare not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl,azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms inthe ring(s) of the heteroaryl group can be oxidized to form a carbonyl,an N-oxide, or a sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized, provided the aromatic nature of thering is preserved. In some embodiments, the heteroaryl group has from 3to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms,from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms. In someembodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroarylgroup has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

As used herein, the term “heteroarylalkyl”, employed alone or incombination with other terms, refers to a group of formulaheteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heteroaryl portion is amonocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl portion has 5 to 10 carbon atoms.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzyl-amine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. Example synthetic methodsfor preparing compounds of the invention are provided in the Schemesbelow.

A series of urea derivatives of formula 5 can be prepared by the methodsoutlined in Scheme 1. Compound 2 can be prepared by treating suitableamines R⁹NH₂ with aldehyde 1; followed by reductive amination withaniline 3 to provide diamino compound 4. Cyclization of diamino compound4 with triphosgene or equivalent including, but not limited to,carbonyldiimidazole (CDI), phosgene, diphosgene, etc. can afford theurea derivatives of formula 5.

Similarly, a series of urea derivatives of formula 9 can be prepared bythe methods outlined in Scheme 2. The ketone 6 can be obtained byreaction of the aldehyde 1 with appropriate Grignard reagent R²MgX oralkyllithium R²Li followed by oxidation. Conversion of the ketone 6 tothe corresponding amino ketone 7 can be achieved by displacement of thechlorine with an appropriate amine R⁹NH₂. The diamino derivative 8 canbe obtained by reductive amination of the ketone 7 with aniline 3 usinga suitable reducing agent such as, but not limited to, sodiumcyanoborohydride, or sodium borohydride. Cyclization of diamino compound8 with triphosgene or carbonyldiimidazole (CDI), phosgene, diphosgene,etc. can afford the urea derivatives of formula 9.

A series of aniline derivatives 14 can be prepared according to theprocedures outlined in Scheme 3. Displacement of fluorine in compound 10with benzylamine (BnNH₂) provides the aniline 11 which can be convertedto bis-ether by reacting with a suitable sodium alkoxide (NaOR where Ris, e.g., methyl, alkyl, or R^(a1)) followed by saponification toprovide acid 12. Compound 13 can be obtained by de-carboxylation ofbenzoic acid 12, followed by hydrogenation to remove the protectinggroup to afford aniline 14.

A series of aniline derivatives 18 can be prepared according to theprocedures outlined in Scheme 4. Compound 16 can be obtained bytreatment of the aniline 15 (where R=methyl or alkyl) with aceticanhydride or acetyl chloride at low temperature. Treatment of compound16 with sulfuryl chloride can afford compound 17 which can be thenconverted to the aniline derivatives 18 by removal of the acetyl groupunder basic conditions.

A series of aniline derivatives 21 can be prepared according to theprocedures outlined in Scheme 5. Treatment of compound 16 withSelectfluor® can provide the desired mono-fluoride 19 which can then beconverted to compound 20 by treating with sulfuryl chloride. The acetylgroup of 20 can be removed under basic conditions to give the anilinederivatives 21.

A series of 1H-pyrrolo[2,3-b]pyridine urea derivatives 26 can beprepared according to the procedures outlined in Scheme 6. Protection ofthe 1H-pyrrolo[2,3-b]pyridine urea 22, which can be prepared accordingto the procedures described in Scheme 1, with suitable protectionreagents such as PhSO₂Cl under basic conditions can afford thecorresponding protected urea 23. The urea halide 24 (L=halo) can beprepared by treatment of the urea 23 with a strong base such as, but notlimited to, LDA, LiHMDS, NaHMDS or butyllithium in an inert solvent suchas THF, ether, or HMPA at low temperature to provide the metallatedintermediate, and followed by treatment with a halogen reagent such asiodine, bromine, 1,2-dibromo-1,1,2,2-tetrachloroethane, NBS or NIS.Deprotection of the urea halide 24 can give the correspondingdeprotected product 25, which can be further converted to the desiredurea derivatives 26 by Suzuki coupling with an appropriate boronic acidor ester R¹⁰B(OR″)₂ (R″=H or alkyl).

Alternatively, a series of 1H-pyrrolo[2,3-b]pyridine urea derivatives 30can be prepared according to the procedures outlined in Scheme 7.Compound 27 can be prepared using procedures as described in the Scheme6. Chlorination of compound 27 with sulfuryl chloride can givedichloride 28 (X¹=X²=Cl). Treating compound 27 with Selectfluor® canyield fluoro-substituted compound 28 (X¹=X²=F). The protecting group ofcompound 28 can be removed then followed by Suzuki coupling of compound29 with an appropriate boronic acid or ester R¹⁰B(OR″)₂ (R″=H or alkyl)as described above to provide 1H-pyrrolo[2,3-b]pyridine urea derivatives30.

A series of amide derivatives 33 can be prepared according to themethods outlined in Scheme 8. The carboxylic acid 31 can be obtained bytreating the protected urea 23 with a strong base such as, but notlimited to, LDA, LiHMDS, NaHMDS, or butyllithium in an inert solventsuch as THF, ether, or HMPA at low temperature, and followed by additionof dry-ice to the reaction mixture. Deprotection of the carboxylic acid31 yields the corresponding acid 32, which can be converted to the amide33 by coupling with an appropriate amine (e.g., NHR^(c3)R^(d3)) in thepresence of a suitable amide coupling reagent such as, but not limitedto, HATU, HBTU, BOP, EDCI/HOBT, EDCI/HOAT, or CDI. Alternatively, theamide 33 can be obtained by conversion of the acid 32 to thecorresponding chloride by treating with oxalyl chloride or thionylchloride followed by reacting with the appropriate amine.

A series of urea derivatives 37 can be prepared according to theprocedures outlined in Scheme 9. Protection of the1H-pyrrolo[2,3-b]pyridine urea 34 can be achieved by reacting withsuitable protection reagent (PG) under basic conditions to afford theurea 35. Alkylation of the urea 35 with an alkyl halide (e.g.,R⁹-halide) under basic conditions can yield the correspondingsubstituted urea 36, followed by removal of the protection group PGunder conditions standard in the art to provide the final compound 37.

A series of urea derivatives 41 can be prepared according to theprocedures outlined in Scheme 10. Urea 38 can be treated with pyridiniumtribromide or bromine to give the dibromo and/or monobromo intermediates39 and 40, respectively, which can be then subjected to a Zn/aceticacid-mediated reduction to afford the urea derivatives 41.

A series of 3H-imidazo[4,5-b]pyridine urea derivatives 50 can beprepared according to the procedures outlined in Scheme 11. Condensationof the pyridinyl diamine 42 (CAS #1131604-99-3) with an appropriate acidR¹⁰COOH under acidic condition such as H₃PO₄ or polyphosphoric acid(PPA) at elevated temperature can yield 3H-imidazo[4,5-b]pyridine 43.The free NH functional group of compound 43 can be protected by treatingit with PG-Cl such as (but not limited to) MeOCH₂Cl or SEMCl, underbasic conditions. Palladium catalyzed coupling of compound 44 withtributyl(vinyl)stannane can afford compound 45 which can be thensubjected to ozonolysis to give the corresponding aldehyde 46. Thechlorine in compound 46 can be displaced with an appropriate amine R⁹NH₂to yield the corresponding amino aldehyde 47. The diamino derivative 48can be obtained by reductive amination of the amino aldehyde 47 withaniline 3 using a suitable reducing agent such as, but not limited to,sodium cyanoborohydride, or sodium borohydride. Cyclization ofdiaminocompound 48 with triphosgene can afford the urea derivatives 49.Removal of the protecting group PG in 49 can give the urea derivatives50.

A series of urea derivatives 51 can be prepared according to theprocedures outlined in Scheme 12. The free NH functional group ofcompound 52 (R¹⁴=H, CAS #1034769-88-4) can be protected by a suitableprotecting group to afford the protected product 53. Palladium catalyzedcoupling of compound 53 with tributyl(vinyl)stannane can afford compound54 which can then be subjected to ozonolysis to give the correspondingaldehyde 55. The chlorine group of 55 can be displaced with anappropriate amine R⁹NH₂ to yield the corresponding amino aldehyde 56.The diamino derivative 57 can be obtained by reductive amination of theamino aldehyde 56 with aniline 3 using a suitable reducing agent suchas, but not limited to, sodium cyanoborohydride, or sodium borohydride.Cyclization of the diamino compound 57 with triphosgene or equivalentcan afford the urea derivatives 58. Removal of the protecting group of58 can provide the urea derivatives 51.

Compounds of the invention having thieno[3,2-b]pyridine cores can alsobe made according to Scheme 12 starting with6-bromo-7-chlorothieno[3,2-b]pyridine (CAS #875340-63-9) in place of 52.

A series of urea derivatives of Formula 5 can be alternatively preparedby the procedures outlined in Scheme 13. Reductive amination of aldehydederivatives 1 with aniline 3 can generate the chloro-compound 59.Palladium-catalyzed amination of compound 59 can afford thediamino-compound 4. The urea derivative 5 can be obtained byintramolecular cyclization of compound 4 with triphosgene or equivalent.

A series of aza-oxindole derivatives 62 can be prepared according to theprocedures outlined in Scheme 14. Alkylation of compound 60, which canbe prepared from compound 36 using similar conditions as described inScheme 10, under basic conditions such as but not limited to Cs₂CO₃, NaHand etc. can generate compound 61. Removal of the protecting group canafford the aza-oxindole derivatives 62.

A series of lactam derivatives 64 can be prepared according to theprocedures outlined in Scheme 15. Palladium catalyzed coupling ofchloro-compound 59 with potassium ethyl malonate or equivalent, followedby in situ intramolecular cyclization can generate the lactam 63, whichcan be then alkylated to afford the lactam derivative 64.

A series of cyclic carbamate derivatives 67 can be prepared according tothe procedures outlined in Scheme 16. Displacement of the chloride incompound 59 by alkoxide under basic conditions can form compound 65,which can react with chloroformate or equivalent to give the carbamatecompound 66. Removal of the protecting group followed by in situcyclization of compound 66 can afford the cyclic carbamate derivative67.

A series of pyrazolo[3,4-b]pyridine urea derivatives 51 can be preparedalternatively according to the procedures outlined in Scheme 17.Halogenation of compound 68, which can be generated by using proceduresas described in Scheme 12 or Scheme 13, with a suitable reagent such as,but not limited to NCS, NBS or NIS can give the corresponding halide 69(L=Cl, Br or I). Coupling of the halide 69 with R¹⁴-M, where M is aboronic acid, boronic ester or an appropriately substituted metalreagent (e.g., M is B(OR)₂, SnBu₃ or ZnBr), under standard Suzuki,Stille or Negishi coupling conditions can give compound 51.

A series of tricyclic amino-derivatives 74 can be prepared according tothe procedures outlined in Scheme 18. Protection of the1H-pyrrolo[2,3-b]pyridine derivative 70 with suitable protectingreagents such as, for example, PhSO₂Cl under basic conditions can affordthe corresponding protected compound 71. Treatment of compound 71 with astrong base such as, for example, lithium diisopropylamide (LDA),butyllithium, or lithium bis(trimethylsilyl)amide (LiHMDS) in an inertsolvent such as THF at low temperature can afford the metallatedintermediate, which can be quenched with a suitable formyl-reagent suchas, for example, dimethylformamide (DMF) to provide the aldehydederivative 72. The amino-derivative 74 can be prepared by reductiveamination of aldehyde 72 with an appropriate amine (e.g. NHR^(c3)R^(d3))to give compound 73, followed by removal of the PhSO₂-protecting groupin the presence of a suitable base such as, for example, K₂CO₃, KOH,KO^(t)Bu, or tetra-n-butylammonium fluoride (TBAF).

Alternatively, compound 74 can be prepared according to the proceduresoutlined in Scheme 19. Removal of the PhSO₂-protecting group in compound72 in the presence of a suitable base such as, for example, K₂CO₃, KOH,KO^(t)Bu or tetra-n-butylammonium fluoride (TBAF), can generate compound75. Reductive amination of aldehyde 75 with an appropriate amine (e.g.NHR^(c3)R^(d3)) can give compound 74.

A series of tricyclic amino-derivatives 80 can be prepared according tothe procedures outlined in Scheme 20. Suzuki coupling of compound 76(L=halogen), which can be prepared using similar procedures as describedin Scheme 6, with an appropriate boronic acid or ester can provide thevinylether derivative 77, which then can be hydrolyzed in aqueous acidicconditions to give the aldehyde derivative 78. Reductive amination ofaldehyde 78 with an appropriate amine (e.g. NHR^(c3)R^(d3)) can givecompound 79, followed by removal of the PhSO₂-protecting group in thepresence of a suitable base such as, for example, K₂CO₃, KOH, KO^(t)Buor tetra-n-butylammonium fluoride (TBAF), to provide theamino-derivatives 80.

Methods of Use

Compounds of the invention can inhibit activity of one or more FGFRenzymes. For example, the compounds of the invention can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of a compound of the invention to the cell,individual, or patient.

In some embodiments, the compounds of the invention are inhibitors ofone or more of FGFR1, FGFR2, FGFR3, and FGFR4. In some embodiments, thecompounds of the invention inhibit each of FGFR1, FGFR2, and FGFR3. Insome embodiments, the compounds of the invention are selective for oneor more FGFR enzymes. In some embodiments, the compounds of theinvention are selective for one or more FGFR enzymes over VEGFR2. Insome embodiments, the selectivity is 2-fold or more, 3-fold or more,5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.

As FGFR inhibitors, the compounds of the invention are useful in thetreatment of various diseases associated with abnormal expression oractivity of FGFR enzymes or FGFR ligands.

For example, the compounds of the invention are useful in the treatmentof cancer. Example cancers include bladder cancer, breast cancer,cervical cancer, colorectal cancer, endometrial cancer, gastric cancer,head and neck cancer, kidney cancer, liver cancer, lung cancer (e.g.,adenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas), ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma),stomach cancer, thyroid cancer, skin cancer (e.g., squamous cellcarcinoma).

Further example cancers include hematopoietic malignancies such asleukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., polycythemiavera, essential thrombocythemia, and primary myelofibrosis),Waldenstrom's Macroglubulinemia, hairy cell lymphoma, and Burkett'slymphoma.

Other cancers treatable with the compounds of the invention includeglioblastoma, melanoma, and rhabdosarcoma.

Other cancers treatable with the compounds of the invention includegastrointestinal stromal tumors.

In addition to oncogenic neoplasms, the compounds of the invention canbe useful in the treatment of skeletal and chondrocyte disordersincluding, but not limited to, achrondroplasia, hypochondroplasia,dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II),Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndromes.

The compounds of the invention may further be useful in the treatment offibrotic diseases, such as where a disease symptom or disorder ischaracterized by fibrosis. Example fibrotic diseases include livercirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis,rheumatoid arthritis, and wound healing.

In some embodiments, the compounds of the invention can be used in thetreatment of a hypophosphatemia disorder such as, for example, X-linkedhypophosphatemic rickets, autosomal recessive hypophosphatemic rickets,and autosomal dominant hypophosphatemic rickets, or tumor-inducedosteromalacia.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)preventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease; 2) inhibiting the disease;for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology), or 3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology).

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, chemotherapeutics or other anti-cancer agents, immuneenhancers, immunosuppressants, immunotherapies, radiation, anti-tumorand anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.),and/or kinase (tyrosine or serine/threonine), epigenetic or signaltransduction inhibitors can be used in combination with the compounds ofthe present invention for treatment of diseases, disorders or conditionsassociated with FGF ligand, receptor or pathway activation. The agentscan be combined with the present compounds in a single dosage form, orthe agents can be administered simultaneously or sequentially asseparate dosage forms.

Suitable agents for use in combination with the compounds of the presentinvention for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this invention may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present invention. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists(e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) andagents that inhibit androgen production (e.g. abiraterone).

Compounds of the present invention may be combined with or in sequencewith other agents against membrane receptor kinases especially forpatients who have developed primary or acquired resistance to thetargeted therapy. These therapeutic agents include inhibitors orantibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 andagainst cancer-associated fusion protein kinases such as Bcr-Abl andEML4-Alk Inhibitors against EGFR include gefitinib and erlotinib, andinhibitors against EGFR/Her2 include but are not limited to dacomitinib,afatinib, lapitinib and neratinib. Antibodies against the EGFR includebut are not limited to cetuximab, panitumumab and necitumumab Inhibitorsof c-Met may be used in combination with FGFR inhibitors. These include(onartumzumab, tivantnib, INC-280). Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compounds ofthe present invention include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors) Inhibitors of JAK (ruxolitinib), Hsp90 (tanespimycin),cyclin dependent kinases (palbociclib), HDACs (panobinostat), PARP(olaparib), and proteasomes (bortezomib, carfilzomib) can also becombined with compounds of the present invention.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with the compounds of thepresent invention include chemotherapy combinations such asplatinum-based doublets used in lung cancer (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, capecitabine,reloxafine, cyclophosphamide, ifosamide, and droloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;leucovorin; tegafur; and haematopoietic growth factors.

Compounds according to the invention may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF).

Other anti-cancer agent(s) include antibody therapeutics tocostimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies tocytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which refers toa combination of a compound of the invention, or its pharmaceuticallyacceptable salt, and at least one pharmaceutically acceptable carrier.These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the FGFR enzyme in tissuesamples, including human, and for identifying FGFR enzyme ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes FGFR enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro FGFR enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the FGFR enzyme. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the FGFR enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more FGFR's as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: 0.025% TFA in acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 1.5 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: 0.1% TFA in acetonitrile; the flow rate was 30 mL/minute, theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature[see “Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B: 0.15%NH₄OH in acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 13-(3,5-Dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: 4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS#958230-19-8) from Adesis, cat #4-263; Synnovator, cat #PBN2011188: 2.71g, 15 mmol) and methylamine (33 wt. % in ethanol, 24 mL, 200 mmol) in2-methoxyethanol (6 mL) was heated to 110° C. and stirred overnight in asealed pressure flask. Then the reaction mixture was cooled to roomtemperature and concentrated. The residue was dissolved in HCl solution(1 N, 25 mL) and heated to 50° C. After stirring for 2 h, the reactionmixture was cooled to room temperature and neutralized with saturatedNaHCO₃ solution. The light yellow precipitate was collected viafiltration, washed with water and hexanes then dried in vacuo to affordthe desired product (2.54 g, 97%) as a light yellow solid. LC-MScalculated for C₉H₁₀N₃O [M+H]⁺ m/z: 176.1; found 176.1.

Step 2:5-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine

To a mixture of 4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(1.75 g, 10 mmol) and 3,5-dimethoxy-benzenamine (2.30 g, 15.0 mmol) inethanol (50 mL) was added acetic acid (8.5 mL, 150 mmol). The resultinglight yellow suspension was heated to reflux. After stirring for 3 h,the resulting red solution was cooled to room temperature and sodiumcyanoborohydride (1.9 g, 30 mmol) was added. The reaction mixture wasstirred at room temperature overnight then neutralized with saturatedNa₂CO₃ solution. The mixture was extracted with ethyl acetate (EtOAc).The organic layer was washed with water and brine then dried overNa₂SO₄. The solvent was removed under reduced pressure. The residue waspurified by column (Biotage®): 40 g silica gel column, eluted with 0 to10% MeOH/DCM to afford the desired product (2.33 g, 75%) as a lightyellow solid. LC-MS calculated for C₁₇H₂₁N₄O₂ [M+H]⁺ m/z: 313.2; found313.1.

Step 3:3-(3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of5-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine(16 mg, 0.05 mmol) and triethylamine (21 μL, 0.15 mmol) intetrahydrofuran (1.5 mL) was added triphosgene (18 mg, 0.06 mmol) intetrahydrofuran (0.5 mL) at 0° C. The resulting yellow suspension wasstirred at 0° C. for 30 min then NaOH solution (1 N, 1 mL) was added.All the precipitate dissolved to afford two layers of solutions and thereaction mixture was stirred at 0° C. for another 30 min. The organiclayer containing the desired product was purified by RP-HPLC (pH=2) toafford the desired product as a white solid. LC-MS calculated forC₁₈H₁₉N₄O₃ [M+H]⁺ m/z: 339.1; found: 339.1.

Example 23-(3,5-Dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 1 with ammonium hydroxide solution replacing methylamine andthe reaction temperature raised to 130° C. in Step 1. LC-MS calculatedfor C₁₇H₁₇N₄O₃ [M+H]⁺ m/z: 325.1; found: 325.1.

Example 33-(3,5-Dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 1 with ethylamine (2 M in THF) replacing methylamine and thereaction temperature raised to 130° C. in Step 1. LC-MS calculated forC₁₉H₂₁N₄O₃ [M+H]⁺ m/z: 353.2; found: 353.1. ¹H NMR (500 MHz, DMSO) δ12.18 (s, 1H), 8.12 (s, 1H), 7.58-7.53 (m, 1H), 6.75 (d, J=2.9 Hz, 1H),6.56 (d, J=2.2 Hz, 2H), 6.42 (t, J=2.2 Hz, 1H), 4.86 (s, 2H), 4.21 (q,J=6.9 Hz, 2H), 3.75 (s, 6H), 1.38 (t, J=6.9 Hz, 3H).

Example 41-Cyclopropyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 1 with cyclopropylamine replacing methylamine and thereaction temperature raised to 130° C. in Step 1. LC-MS calculated forC₂₀H₂₁N₄O₃ [M+H]⁺ m/z: 365.2; found: 365.2. ¹H NMR (500 MHz, DMSO) δ12.20 (s, 1H), 8.16 (s, 1H), 7.55-7.51 (m, 1H), 7.03 (d, J=2.5 Hz, 1H),6.54 (d, J=2.2 Hz, 2H), 6.39 (t, J=2.2 Hz, 1H), 4.77 (s, 2H), 3.74 (s,6H), 3.39-3.33 (m, 1H), 1.14-1.08 (m, 2H), 0.76-0.66 (m, 2H).

Example 51-(Cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 1 with cyclopropylmethylamine replacing methylamine and thereaction temperature raised to 130° C. in Step 1. LC-MS calculated forC₂₁H₂₃N₄O₃ [M+H]⁺ m/z: 379.2; found: 379.1.

Example 61-Benzyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 1 with benzylamine replacing methylamine and the reactiontemperature raised to 130° C. in Step 1. LC-MS calculated for C₂₄H₂₃N₄O₃[M+H]⁺ m/z: 415.2; found: 415.2.

Example 73-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of5-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine(Example 1, step 2: 2.33 g, 7.46 mmol) and triethylamine (3.1 mL, 22mmol) in tetrahydrofuran (50 mL) was added triphosgene (2.66 g, 8.95mmol) in tetrahydrofuran (20 mL) at 0° C. The resulting yellowsuspension was stirred at 0° C. for 30 min then NaOH solution (1 N, 20mL) was added. All the precipitate dissolved to give two layers ofsolutions and the reaction mixture was stirred at 0° C. for another 30min. The mixture was extracted with ethyl acetate (EtOAc). The organiclayers were combined and washed with water, brine then dried overNa₂SO₄. The solvents were removed under reduced pressure. The residuewas dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. then sodiumhydride (60 wt. % dispersion in mineral oil, 600 mg, 15 mmol) was addedin three portions. The resulting brown solution was stirred at 0° C. for30 min then benzensulfonyl chloride (1.4 mL, 11 mmol) was addeddropwise. After stirring at 0° C. for 30 min, the reaction was quenchedwith water and the mixture was extracted with EtOAc. The organic layerswere combined and washed with water, brine then dried over Na₂SO₄. Thesolvents were removed under reduced pressure and the residue waspurified by column (Biotage®): 40 g silica gel column, eluted with 20 to50% EtOAc/Hexanes to give a light yellow solid which was triturated withdiethyl ether to give the pure product (2.75 g, 77%) as a white solid.LC-MS calculated for C₂₄H₂₃N₄O₅S [M+1]⁺ m/z: 479.1; found: 479.1.

Step 2:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(29 mg, 0.06 mmol) in acetonitrile (3 mL, 60 mmol) at 0° C. was addedsulfuryl chloride (7.36 μL, 0.09 mmol) in dichloromethane (0.2 mL)dropwise over 5 min. The resulting light yellow solution was stirred at0° C. for 10 min, at which time LC-MS indicated complete consumption ofthe starting material. The reaction was quenched with saturated NaHCO₃solution at 0° C. then extracted with EtOAc. The organic layer waswashed with water, brine and dried over Na₂SO₄. The solvent was removedunder reduced pressure. The residue and potassium carbonated (50 mg,0.36 mmol) were dissolved in methanol (9.5 mL) and water (0.5 mL). Theresulting solution was heated to 65° C. and stirred for 2 h. The mixturewas purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₁₈H₁₈ClN₄O₃ [M+H]⁺ m/z: 373.1; found:373.2. ¹H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 8.07 (s, 1H), 7.53-7.48(m, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.73 (d, J=2.7Hz, 1H), 4.89 (d, J=13.4 Hz, 1H), 4.66 (d, J=13.4 Hz, 1H), 3.87 (s, 3H),3.80 (s, 3H), 3.66 (s, 3H).

Example 83-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was formed in the same reaction as described for Example7, Step 2. Purified by RP-HPLC (pH=2) to afford the pure product as awhite solid. LC-MS calculated for C₁₈H₁₇Cl₂N₄O₃ [M+H]⁺ m/z: 407.1;found: 407.1. ¹H NMR (500 MHz, DMSO) δ 12.07 (s, 1H), 8.06 (s, 1H),7.53-7.48 (m, 1H), 7.00 (s, 1H), 6.86 (d, J=2.6 Hz, 2H), 4.73 (s, 2H),3.96 (s, 6H), 3.66 (s, 3H).

Example 93-(2,4-Dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was formed as a minor-product in the same reaction asdescribed for Example 7, Step 2. Purified by RP-HPLC (pH=2) to affordthe pure compound as a white solid. LC-MS calculated for C₁₈H₁₇Cl₂N₄O₃[M+H]⁺ m/z: 407.1; found: 407.0. ¹H NMR (500 MHz, DMSO) δ 11.96 (s, 1H),8.05 (s, 1H), 7.51-7.46 (m, 1H), 7.28 (s, 1H), 6.83 (br, 1H), 4.95 (d,J=12.9 Hz, 1H), 4.69 (d, J=12.9 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H),3.66 (s, 3H).

Example 103-(3,5-Dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: Preparation of Lithium Diisopropylamide (LDA) Solution (1 M inTHF)

To a cooled (−78° C.) solution of N,N-diisopropylamine (0.14 mL, 1.0mmol) in tetrahydrofuran (0.46 mL) was added n-butyllithium (2.5 M inhexanes, 0.40 mL, 1.0 mmol) dropwise. The mixture was stirred at −78° C.for 5 min then warmed to 0° C. and stirred for 20 min to afford 1 mL of1 M LDA solution in THF.

Step 2:8-bromo-3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a cooled (−78° C.) solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 7, Step 1; 49 mg, 0.10 mmol) in tetrahydrofuran (3 mL) wasadded freshly prepared lithium diisopropylamide (LDA) solution (1 M inTHF, 0.30 mL) dropwise. The resulting solution was stirred at −78° C.for 30 min then a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (37mg, 0.11 mmol) in tetrahydrofuran (0.2 mL) was added. After stirring at−78° C. for 1 h, the reaction was quenched with saturated NH₄Cl solutionat −78° C. then warmed to room temperature. The mixture was extractedwith EtOAc. The organic layers were combined then washed with water,brine and dried over Na₂SO₄. The solvents were removed under reducedpressure. The residue was used in the next step without furtherpurification. LC-MS calculated for C₂₄H₂₂BrN₄O₅S [M+H]⁺ m/z: 557.0;found: 557.1.

Step 3:3-(3,5-dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of8-bromo-3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(12 mg, 0.022 mmol),1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine(from Alfa Aesar, cat #H51659, 13 mg, 0.043 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II) complexedwith dichloromethane (1:1) (4 mg, 0.004 mmol), and potassium carbonate(6.0 mg, 0.043 mmol) was dissolved in 1,4-dioxane (3 mL) then water (0.3mL) was added. The mixture was degassed then back-filled with nitrogen.This process was repeated for three times. The reaction mixture washeated to 90° C. and stirred for 1 h, at which time LC-MS indicated thereaction was complete. The mixture was cooled to room temperature andconcentrated. The residue was purified by column (Biotage®): 12 g silicagel column, eluted with 0 to 10% MeOH/DCM to afford the desired product(12 mg, 86%) as a yellow solid. LC-MS calculated for C₃₅H₃₇N₆O₅S [M+H]⁺m/z: 653.3; found: 653.3.

Step 4:3-(3,5-dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of3-(3,5-dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]-pyrimidin-2-one(12 mg, 0.02 mmol) in tetrahydrofuran (2 mL) was added potassiumt-butoxide (1 M in THF, 0.2 mL). The resulting yellow solution wasstirred at room temperature for 15 min then diluted with methanol andpurified by RP-HPLC (pH=2) to afford the desired product as a yellowsolid. LC-MS calculated for C₂₉H₃₃N₆O₃ [M+H]⁺ m/z: 513.3; found: 513.3.¹H NMR (500 MHz, DMSO) δ 12.27 (s, 1H), 8.00 (s, 1H), 7.89 (d, J=8.8 Hz,2H), 7.15 (s, 1H), 7.11 (d, J=8.9 Hz, 2H), 6.55 (d, J=2.1 Hz, 2H), 6.40(t, J=2.1 Hz, 1H), 4.83 (s, 2H), 3.98 (br, 2H), 3.75 (s, 6H), 3.70 (s,3H), 3.54 (br, 2H), 3.18 (br, 2H), 3.05 (br, 2H), 2.88 (s, 3H).

Example 113-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 10 with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine.LC-MS calculated for C₂₂H₂₃N₆O₃ [M+H]⁺ m/z: 419.2; found: 419.2. ¹H NMR(500 MHz, DMSO) δ 12.34 (s, 1H), 8.22 (s, 1H), 8.01 (d, J=1.6 Hz, 2H),7.02 (d, J=1.5 Hz, 1H), 6.55 (d, J=2.2 Hz, 2H), 6.40 (t, J=2.2 Hz, 1H),4.84 (s, 2H), 3.90 (s, 3H), 3.75 (s, 6H), 3.67 (s, 3H).

Example 123-(3,5-Dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Step 1:3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a cooled (−78° C.) solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(44 mg, 0.092 mmol) in tetrahydrofuran (3 mL) was added LDA solution(freshly prepared, 1M in THF, 0.30 mL, 0.3 mmol) dropwise. The resultingsolution was stirred at −78° C. for 30 min then dry CO₂ gas (preparedfrom dry ice by passing through a drying tube) was bubbled into thereaction mixture for 30 min. The mixture was warmed to room temperatureslowly and acidified with 1 N HCl then extracted with EtOAc. The organiclayer was washed with water, brine then dried over Na₂SO₄. The solventwas removed under reduced pressure. The residue was used in the nextstep without further purification. LC-MS calculated for C₂₅H₂₃N₄O₇S[M+H]⁺ m/z: 523.1; found: 523.2.

Step 2:3-(3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

The crude product from Step 1 andbenzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate(41 mg, 0.092 mmol) were dissolved in tetrahydrofuran (5 mL) thentriethylamine (38 μL, 0.28 mmol) was added. The mixture was stirred atroom temperature for 5 min then methylamine (2 M in THF, 140 μL, 0.28mmol) was added. After stirring at room temperature for 30 min, thereaction mixture was diluted with EtOAc then washed with water, brineand dried over Na₂SO₄. The solvents were removed under reduced pressureand the residue was purified by column (Biotage®): 12 g silica gelcolumn, eluted with 30 to 100% EtOAc/Hexanes to afford the desiredproduct (21 mg, 43%). LC-MS calculated for C₂₆H₂₆N₅O₆S [M+H]⁺ m/z:536.2; found: 536.1.

Step 3:3-(3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To a stirred solution of3-(3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide(21 mg, 0.039 mmol) in tetrahydrofuran (3 mL) was added potassiumtert-butoxide (1 M in THF, 0.4 mL, 0.4 mmol). The resulting yellowsolution was stirred at room temperature for 15 min then diluted withMeOH and purified by RP-HPLC (pH=2) to afford the desired product as awhite solid. LC-MS calculated for C₂₀H₂₂N₅O₄ [M+H]⁺ m/z: 396.2; found:396.2.

Example 133-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:8-bromo-3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a cooled (0° C.) solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(96 mg, 0.20 mmol) in acetonitrile (3 mL) was added a solution ofsulfuryl chloride (16 μL, 0.20 mmol) in methylene chloride (1 mL)dropwise. After stirring at 0° C. for 5 min, the reaction was quenchedwith water then extracted with EtOAc. The organic layer was then washedwith water, brine and dried over Na₂SO₄. The solvent was removed underreduced pressure. The residue was dissolved in tetrahydrofuran (3 mL, 40mmol) and cooled to −78° C. then LDA solution (freshly prepared, 1M inTHF, 0.70 mL, 0.70 mmol) was added. The resulting yellow solution wasstirred at −78° C. for 30 min then a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (72 mg, 0.22 mmol) in 0.5 mL ofTHF was added. The resulting brown solution was stirred at −78° C. for 1h, at which time LC-MS indicated the reaction was complete. The reactionwas quenched with saturated NH₄Cl solution at −78° C. then warmed toroom temperature. The mixture was extracted with EtOAc and the organiclayer was washed with water, brine then dried over Na₂SO₄. The solventwas removed under reduced pressure and the residue was purified byBiotage®: 12 g silica gel column, eluted with 0 to 5% EtOAc/DCM toafford the desired product (45 mg, 38%) as a yellow solid.

Step 2:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of8-bromo-3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(15 mg, 0.025 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10mg, 0.051 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (2 mg, 0.002 mmol) and potassium carbonate(10. mg, 0.076 mmol) was dissolved in 1,4-dioxane (3 mL, 40 mmol) thenwater (0.3 mL, 20 mmol) was added. The mixture was degassed thenback-filled with nitrogen three times. The resulting red solution washeated to 90° C. and stirred for 30 min, at which time LC-MS indicatedthe reaction was complete. The reaction mixture was cooled to roomtemperature and diluted with EtOAc then washed with water and brine. Theorganic layer was dried over Na₂SO₄ and the solvent was removed underreduced pressure. The residue was dissolved in tetrahydrofuran (3 mL)then potassium tert-butoxide (1M in THF, 0.2 mL, 0.2 mmol) was added.The resulting yellow solution was stirred at room temperature for 30 minthen diluted with MeOH and purified by RP-HPLC (pH=2) to afford thedesired product as a white solid. LC-MS calculated for C₂₂H₂₂ClN₆O₃[M+H]⁺ m/z: 453.1; found: 453.1. ¹H NMR (500 MHz, DMSO) δ 12.25 (s, 1H),8.20 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.78(d, J=2.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 4.87 (d, J=13.4 Hz, 1H), 4.64(d, J=13.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.67 (s,3H).

Example 143-(2-Chloro-3,5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:8-bromo-3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of8-bromo-3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(15 mg, 0.025 mmol) in tetrahydrofuran (3 mL) was added potassiumtert-butoxide (1 M in THF, 0.1 mL, 0.1 mmol). After stirring at roomtemperature for 20 min, the reaction was quenched with water thenextracted with EtOAc. The organic layer was washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresidue was used in the next step without further purification. LC-MScalculated for C₁₈H₁₇BrClN₄O₃ [M+H]⁺ m/z: 451.0; found: 451.0.

Step 2:3-(2-chloro-3,5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of the crude product from Step 1,2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol(12 mg, 0.051 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (2mg, 0.002 mmol), and potassium carbonate (10 mg, 0.076 mmol) wasdissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction mixturewas degassed then back-filled with nitrogen three times. The resultingsolution was heated to 90° C. After stirring for 7 h, the reactionmixture was cooled to room temperature and diluted with MeOH, thenfiltered and purified by RP-HPLC (pH=10) to afford the product as ayellow solid. LC-MS calculated for C₂₃H₂₄ClN₆O₄ [M+H]⁺ m/z: 483.2;found: 483.2.

Example 153-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-5-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 14, Step 2 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanoland a reaction time of 2 h. LC-MS calculated for C₂₂H₂₂ClN₆O₃ [M+H]⁺m/z: 453.1; found: 453.1. ¹H NMR (500 MHz, DMSO) δ 12.31 (s, 1H), 8.06(s, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.07 (s, 1H), 6.79 (d, J=2.7 Hz, 1H),6.76 (d, J=1.9 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 4.90 (d, J=13.4 Hz, 1H),4.65 (d, J=13.4 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.70(s, 3H).

Example 163-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile

Step 1:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile

This compound was prepared using procedures analogous to those describedfor Example 13, Step 1 with 4-methylbenzenesulfonylcyanide replacing1,2-dibromo-1,1,2,2-tetrachloroethane. The reaction mixture was purifiedby RP-HPLC (pH=10) to afford the desired product as a white solid.

Step 2:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile

The phenylsulfonyl-protecting group was removed using similar conditionsas described in Example 10, Step 4. The product was purified by RP-HPLC(pH=10) to afford a white solid. LC-MS calculated for C₁₉H₁₇ClN₅O₃[M+H]⁺ m/z: 398.1; found: 398.0.

Example 173-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those describedfor Example 10 with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinereplacing1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-piperazine.Purified by RP-HPLC (pH=2) to afford the pure product as a white solid.LC-MS calculated for C₂₄H₂₈N₅O₃ [M+H]⁺ m/z: 434.2; found: 434.2.

Example 183-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of3-(3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(8 mg, 0.02 mmol) and palladium (10 wt. % on carbon, 10 mg, 0.009 mmol)was dissolved in methanol (5 mL). The reaction mixture was stirred undera balloon of hydrogen at room temperature for 2 h, at which time LC-MSindicated the reaction was complete. The mixture was filtered andpurified by RP-HPLC (pH=2) to afford the product as a white solid. LC-MScalculated for C₂₄H₃₀N₅O₃ [M+H]⁺ m/z: 436.2; found: 436.2.

Example 193-(3,5-Dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Step 1:3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a stirred solution of3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (prepared as described in Example 12, Step 1; 1 eq.) in THF wasadded potassium tert-butoxide (1M in THF, 5 eq.). The resulting mixturewas stirred at room temperature for 20 min then acidified with 1N HCl.The mixture was diluted with water then extracted withdichloromethane/isopropyl alcohol (2:1). The organic layers werecombined and dried over Na₂SO₄. The solvents were removed under reducedpressure and the residue was used in the next step without furtherpurification. LC-MS calculated for C₁₉H₁₉N₄O₅ [M+H]⁺ m/z: 383.1; found:383.1.

Step 2:3-(3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To a solution of3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (13 mg, 0.034 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(16 mg, 0.037 mmol) in N,N-dimethylformamide (4 mL) was addedtriethylamine (50 μL, 0.3 mmol) and dimethylamine (2M in THF, 80 μL, 0.2mmol). The mixture was stirred at room temperature for 30 min, at whichtime LC-MS indicated the reaction was complete. The mixture was dilutedwith MeOH then purified by RP-HPLC (pH=2) to afford the desired productas a white solid. LC-MS calculated for C₂₁H₂₄N₅O₄ [M+H]⁺ m/z: 410.2;found: 410.2.

Example 203-(3,5-Dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedure analogous to those forExample 19, Step 2 with azetidin-3-ol hydrochloride replacingdimethylamine. Purified by RP-HPLC (pH=2) to afford the desired productas a white solid. LC-MS calculated for C₂₂H₂₄N₅O₅ [M+H]⁺ m/z: 438.2;found: 438.2.

Example 213-(3,5-Dimethoxyphenyl)-8-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedure analogous to those forExample 19, Step 2 with 3-pyrrolidinol replacing dimethylamine. Purifiedby RP-HPLC (pH=2) to afford the desired product as a white solid. LC-MScalculated for C₂₃H₂₆N₅O₅ [M+H]⁺ m/z: 452.2; found: 452.2.

Example 223-(3,5-Dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedure analogous to those forExample 19, Step 2 with 1-methyl-piperazine replacing dimethylamine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₄H₂₉N₆O₄ [M+H]⁺ m/z: 465.2; found: 465.2.

Example 233-(2-Chloro-3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Step 1:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a cooled (0° C.) solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(107 mg, 0.224 mmol) in acetonitrile (3 mL) was added a solution ofsulfuryl chloride (18 μL, 0.224 mmol) in methylene chloride (1 mL)dropwise. After stirring at 0° C. for 5 min, the reaction was quenchedwith water then extracted with EtOAc. The organic layer was then washedwith water, brine and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was dissolved in tetrahydrofuran (3 mL)and cooled to −78° C. then LDA solution (freshly prepared, 1 M in THF,0.78 mL, 0.78 mmol) was added. The resulting yellow solution was stirredat −78° C. for 30 min then dry CO₂ gas (prepared from dry ice by passingthrough a drying tube) was bubbled into the reaction mixture for 30 min.The mixture was warmed to room temperature slowly and acidified with 1 NHCl then extracted with EtOAc. The organic layer was washed with water,brine then dried over Na₂SO₄. The solvent was removed under reducedpressure. The residue was used in the next step without furtherpurification. LC-MS calculated for C₂₅H₂₂ClN₄O₇S [M+H]⁺ m/z: 557.1;found: 557.1.

Step 2:3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a solution of3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (20 mg, 0.04 mmol) in tetrahydrofuran (3 mL, 40 mmol) was addedpotassium tert-butoxide (1 M in THF, 0.2 mL, 0.2 mmol). The resultingyellow solution was stirred at room temperature for 30 min then quenchedwith water and acidified with 1 N HCl. The mixture was extracted withEtOAc. The organic layers were combined then washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure to affordthe crude product which was used in the next step without furtherpurification. LC-MS calculated for C₁₉H₁₈ClN₄O₅ [M+H]⁺ m/z: 417.1;found: 417.1.

Step 3:3-(2-chloro-3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To a solution of the crude product from Step 2 andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(17 mg, 0.039 mmol) in N,N-dimethylformamide (4 mL) was addedtriethylamine (25 μL, 0.18 mmol) and methylamine (2M in THF, 54 μL, 0.11mmol). The mixture was stirred at room temperature for 30 min, at whichtime LC-MS indicated the reaction was complete. The mixture was dilutedwith MeOH then purified by RP-HPLC (pH=10) to afford the desired productas a white solid. LC-MS calculated for C₂₀H₂₁ClN₅O₄ [M+H]⁺ m/z: 430.1;found: 430.1. ¹H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 8.46 (d, J=4.6 Hz,1H), 8.06 (s, 1H), 7.46 (s, 1H), 6.78 (d, J=2.7 Hz, 1H), 6.72 (d, J=2.7Hz, 1H), 4.86 (d, J=13.4 Hz, 1H), 4.64 (d, J=13.4 Hz, 1H), 3.87 (s, 3H),3.80 (s, 3H), 3.66 (s, 3H), 2.83 (d, J=4.6 Hz, 3H).

Example 243-(2-Chloro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

This compound was prepared using procedures analogous to those forExample 23, Step 3 with dimethylamine (2 M in THF) replacingmethylamine. Purified by RP-HPLC (pH=2) to afford the desired product asa white solid. LC-MS calculated for C₂₁H₂₃ClN₅O₄ [M+H]⁺ m/z: 444.1;found: 444.1.

Example 253-(2-Chloro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedure analogous to those forExample 23, Step 3 with azetidin-3-ol hydrochloride replacingmethylamine. Purified by RP-HPLC (pH=2) to afford the desired product asa white solid. LC-MS calculated for C₂₂H₂₃ClN₅O₅ [M+H]⁺ m/z: 472.1;found: 472.2.

Example 263-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 23, Step 3 with 1-methyl-piperazine replacing methylamine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₄H₂₈ClN₆O₄ [M+H]⁺ m/z: 499.2; found:499.2. ¹H NMR (500 MHz, DMSO) δ 11.50 (br, 1H), 8.31 (s, 1H), 7.32 (s,1H), 6.80 (d, J=2.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 4.95 (d, J=13.9 Hz,1H), 4.73 (d, J=13.9 Hz, 1H), 4.50 (br, 2H), 3.86 (s, 3H), 3.79 (s, 3H),3.72 (s, 3H), 3.52 (br, 2H), 3.42 (br, 2H), 3.13 (br, 2H), 2.87 (s, 3H).

Example 27N-Cyclopropyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Step 1:3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a stirred solution of3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (125 mg, 0.239 mmol) in acetonitrile (5 mL) was added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (from Aldrich, cat #439479, 102 mg, 0.287 mmol). Theresulting yellow solution was stirred at room temperature for 2 h, atwhich time LCMS indicated completion of the reaction to the desiredproduct. The reaction mixture was diluted with EtOAc then washed withwater and brine. The organic layer was dried over Na₂SO₄ thenconcentrated. The residue was dissolved in tetrahydrofuran (5 mL) thenpotassium tert-butoxide (1M in THF, 1.2 mL, 1.2 mmol) was added. Themixture was stirred at room temperature for 20 min then acidified with 1N HCl. The mixture was extracted with DCM/IPA (2:1) and the organiclayer was dried over Na₂SO₄ and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₁₉H₁₈FN₄O₅ [M+H]⁺ m/z: 401.1; found: 401.1.

Step 2:N-cyclopropyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To a solution of3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (6 mg, 0.015 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(8 mg, 0.018 mmol) in N,N-dimethylformamide (2.5 mL) was addedtriethylamine (20 μL, 0.1 mmol) and cyclopropylamine (5.2 μL, 0.075mmol). The resulting yellow solution was stirred at room temperature for30 min, at which time LC-MS indicated the reaction was complete. Themixture was diluted with MeOH then purified by RP-HPLC (pH=2) to affordthe desired product as a white solid. LC-MS calculated for C₂₂H₂₃FN₅O₄[M+H]⁺ m/z: 440.2; found: 440.1.

Example 283-(2-Fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 27, Step 2 with azetidin-3-ol hydrochloride replacingcyclopropylamine. Purified by RP-HPLC (pH=2) to afford the desiredproduct as a white solid. LC-MS calculated for C₂₂H₂₃FN₅O₅ [M+H]⁺ m/z:456.2; found: 456.2.

Example 291-{[3-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]carbonyl}pyrrolidine-3-carbonitrile

This compound was prepared using procedures analogous to those forExample 27, Step 2 with pyrrolidine-3-carbonitrile hydrochloridereplacing cyclopropylamine. Purified by RP-HPLC (pH=2) to afford thedesired product as a white solid. LC-MS calculated for C₂₄H₂₄FN₆O₄[M+H]⁺ m/z: 479.2; found: 479.2.

Example 303-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 27, Step 2 with 1-methyl-piperazine replacing cyclopropylamine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₄H₂₈FN₆O₄ [M+H]⁺ m/z: 483.2; found: 483.2.¹H NMR (500 MHz, DMSO) δ 12.32 (s, 1H), 8.11 (s, 1H), 7.07 (s, 1H), 6.69(dd, J=6.7, 2.9 Hz, 1H), 6.62 (dd, J=6.7, 2.9 Hz, 1H), 4.81 (s, 2H),4.50 (br, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.65 (s, 3H), 3.49 (br, 2H),3.39 (br, 2H), 3.14 (br, 2H), 2.86 (s, 3H).

Example 313-(2-Fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxypiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 27, Step 2 with piperidin-3-ol replacing cyclopropylamine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₄H₂₇FN₅O₅ [M+H]⁺ m/z: 484.2; found: 484.2.

Example 323-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 7, Step 1: 63.0 mg, 0.132 mmol) in acetonitrile (9 mL) wasadded 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (95.6 mg, 0.270 mmol). The suspension was stirred atroom temperature overnight. Then the resulting solution was concentratedto remove solvents. The residue was dissolved in AcOEt, and washed withNaHCO₃ aqueous solution, brine then dried over MgSO₄. The solvents wereremoved under reduced pressure to afford the desired compound which wasused in the next step without further purification. LC-MS calculated forC₂₄H₂₂FN₄O₅S [M+H]⁺ m/z: 497.1; found: 497.1.

Step 2:3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of the above residue in Step 1 in THF (2 mL) was added 1.0M potassium tert-butoxide in THF (390 μL, 0.39 mmol). The solution wasstirred at r.t. 30 min, then concentrated to remove solvent. The residuewas dissolved in MeOH and purified by RP-HPLC (pH=2) to afford thedesired product. LC-MS calculated for C₁₈H₁₈FN₄O₃ [M+H]⁺ m/z: 357.1;found: 357.1. ¹H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 8.08 (s, 1H),7.53-7.49 (m, 1H), 6.85 (d, J=2.3 Hz, 1H), 6.70 (dd, J=6.7, 2.9 Hz, 1H),6.63 (dd, J=5.2, 2.9 Hz, 1H), 4.82 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H),3.65 (s, 3H).

Example 333-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was formed in the same reaction as described for Example32. LC-MS calculated for C₁₈H₁₇F₂N₄O₃ [M+H]⁺ m/z: 375.1; found: 375.2.¹H NMR (500 MHz, DMSO) δ 11.98 (s, 1H), 8.03 (s, 1H), 7.52-7.46 (m, 1H),7.04 (t, J=8.1 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 4.78 (s, 2H), 3.89 (s,6H), 3.65 (s, 3H).

Example 343-(2-Fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Step 1:3-(2-fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To a solution of N,N-diisopropylamine (1.0E2 μL, 0.76 mmol) in THF (0.5mL) was added 2.5 M n-butyllithium in hexanes (0.30 mL, 0.76 mmol)dropwise at −78° C. The mixture was stirred at −78° C. for 5 min, thenwarmed up to 0° C. and stirred for 20 min. then cooled to −78° C. again.

To a solution of3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(75.0 mg, 0.151 mmol) (mixed with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one,Example 32, Step 1) in tetrahydrofuran (1.0 mL) was added prepared LDAsolution dropwise at −78° C. The resulting yellow suspension was stirredat −78° C. for 50 min, then a solution of N,N-dimethylcarbamoyl chloride(70 μL, 0.76 mmol) in tetrahydrofuran (1.0 mL) was added dropwise. Thereaction mixture was stirred at −20° C. for 1 hour then quenched withsaturated NH₄Cl solution, and then extracted with AcOEt twice. Thecombined organic phase was washed with brine and dried over MgSO₄, Thesolvents were removed under reduced pressure to afford the desiredcompound which was used in the next step without further purification.LC-MS calculated for C₂₇H₂₇FN₅O₆S [M+H]⁺ m/z: 568.2; found: 568.2.

Step 2:3-(2-fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

To as solution of the above residue made in Step 1 in THF (2 mL) wasadded 1.0 M potassium tert-butoxide in THF (450 μL, 0.45 mmol). Thesolution was stirred at r.t. 30 min, then concentrated to removesolvent. The residue was dissolved in MeOH and purified by RP-HPLC(pH=2) to afford the desired product. LC-MS calculated for C₂₁H₂₃FN₅O₄[M+H]⁺ m/z: 428.2; found: 428.2. ¹H NMR (500 MHz, DMSO) δ 12.27 (s, 1H),8.10 (s, 1H), 7.07 (s, 1H), 6.72-6.66 (m, 1H), 6.64-6.60 (m, 1H), 4.81(s, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.64 (s, 3H), 3.35-2.95 (m, 6H).

Example 353-(2,6-Difluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

This compound was formed in the same reaction as described for Example34, LC-MS calculated for C₂₁H₂₂F₂N₅O₄ [M+H]⁺ m/z: 446.2; found: 446.2.¹H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 8.07 (s, 1H), 7.08-7.00 (m, 2H),4.78 (s, 2H), 3.89 (s, 6H), 3.65 (s, 3H), 3.36-2.92 (m, 6H).

Example 363-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(290.0 mg, 0.5841 mmol) in acetonitrile (8 mL) was added a solution ofsulfuryl chloride (49.6 μL, 0.613 mmol) in methylene chloride (2 mL)dropwise at 0° C. The resulting solution was stirred at 0° C. for 10min. The reaction was quenched with water then extracted with EtOAc. Theorganic layer was then washed with water, brine and dried over Na₂SO₄.The solvents were removed under reduced pressure to afford the desiredcompound which was used in the next step without further purification.LC-MS calculated for C₂₄H₂₁ClFN₄O₅S [M+H]⁺ m/z: 531.1; found: 531.1.

Step 2:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of the above residue formed in Step 2 in THF (3 mL) wasadded 1.0 M potassium tert-butoxide in THF (1.8 mL, 1.8 mmol). Thesolution was stirred at r.t. 30 min, then concentrated to removesolvent. The residue was dissolved in MeOH and purified by RP-HPLC(pH=2) to afford the desired product. LC-MS calculated for C₁₈H₁₇ClFN₄O₃[M+H]⁺ m/z: 391.1; found: 391.1. ¹H NMR (500 MHz, DMSO) δ 12.10 (s, 1H),8.07 (s, 1H), 7.52 (s, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.86 (d, J=3.2 Hz,1H), 4.79-4.71 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H).

Example 373-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:9,9-Dibromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dioneand9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Pyridinium tribromide (120 mg, 0.37 mmol) was added to a mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(40.0 mg, 0.107 mmol) in tert-butyl alcohol (1.2 mL) and then thereaction was stirred at 30° C. overnight. The mixture was diluted withethyl acetate, washed with saturated NaHCO₃, water, brine, dried overNa₂SO₄, filtered, and then concentrated to provide the crude product asa mixture of the above two products which were used in the next stepdirectly. LCMS (M+H)⁺: m/z=549.0, 471.0.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Zinc (10 mg, 0.2 mmol) was added to a mixture of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione(10.0 mg, 0.0213 mmol) and9,9-dibromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione(10.0 mg, 0.0182 mmol) in methanol (0.3 mL)/acetic acid (0.3 mL), thenthe mixture was stirred at room temperature for 3 h. The reactionmixture was filtered and then the product was purified by RP-HPLC(pH=2). LC-MS calculated for C₁₈H₁₇F₂N₄O₄ [M+H]⁺ m/z: 391.1; found:391.1. ¹H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 7.82 (s, 1H), 7.03 (t,J=8.1 Hz, 1H), 4.60 (s, 2H), 4.00 (s, 2H), 3.88 (s, 6H), 3.39 (s, 3H).

Example 383-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one

Step 1: 7-chlorothieno[3,2-b]pyridine-6-carbaldehyde

To a solution of ethyl 7-chlorothieno[3,2-b]pyridine-6-carboxylate (CAS#90690-94-1) purchased from Synthonix, Inc, cat #E4282, 409 mg, 1.69mmol) in tetrahydrofuran (5.0 mL) at 0° C. was added diisobutylaluminumhydride (1.0 M in hexane, 5.1 mL, 5.1 mmol). The resulting mixture wasstirred at this temperature for 2 h before it was quenched with MeOH (5mL) and NaHCO₃ solution (10 mL). The aqueous phase was extracted withEtOAc (3×10 mL), and it was dried over Na₂SO₄ and concentrated in vacuo.The crude alcohol was used without further purification. LC-MScalculated for C₈H₇ONSCl [M+H]⁺ m/z: 200.1; found 200.1.

To a solution of the alcohol obtained above in methylene chloride (5.0mL) was added sodium bicarbonate (710 mg, 8.5 mmol) and Dess-Martinperiodinane (860 mg, 2.0 mmol). The resulting mixture was stirred for 1h before it was quenched with Na₂S₂O₃ solution (5 mL) and NaHCO₃solution (5 mL). The aqueous phase was extracted with methylene chloride(3×10 mL), dried over Na₂SO₄, and concentrated in vacuo. The crudemixture was purified by flash column (MeOH/DCM, 3%˜20%) to afford thealdehyde (237 mg, 72% for two steps) as a white solid. LC-MS calculatedfor C₈H₅ONSCl [M+H]⁺ m/z: 198.1; found 198.1.

Step 2: 7-(methylamino)thieno[3,2-b]pyridine-6-carbaldehyde

A solution of 7-chlorothieno[3,2-b]pyridine-6-carbaldehyde (237 mg, 1.20mmol) in methylamine (33% in ethanol, 2.0 mL, 16.0 mmol) was heated to110° C. for 3 h. After cooling to room temperature, the solution wasconcentrated in vacuo. The crude imine was dissolved in hydrogenchloride (1.0 M in water, 3.6 mL, 3.6 mmol), and the resulting mixturewas stirred at 60° C. for 3 h. The solution was neutralized with NaOH(2.0 M, 1.7 mL, 3.4 mmol) and NaHCO₃ sat. solution. After it wasfiltered and dried over high vacuum, the pure7-(methylamino)thieno[3,2-b]pyridine-6-carbaldehyde (150 mg, 65%) wasobtained as a yellow solid. LC-MS calculated for C₉H₉ON₂S [M+H]⁺ m/z:193.2; found 193.2.

Step 3:6-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methylthieno[3,2-b]pyridin-7-amine

To a solution of 7-(methylamino)thieno[3,2-b]pyridine-6-carbaldehyde (75mg, 0.39 mmol) in ethanol (3.0 mL) was added 3,5-dimethoxyaniline (120mg, 0.78 mmol) and acetic acid (0.223 mL, 3.92 mmol). The resultingmixture was stirred at 90° C. for 2 h before it was cooled to roomtemperature. Sodium cyanoborohydride (120 mg, 2.0 mmol) was added to thesolution and the mixture was stirred for another 2 h. The reactionmixture was diluted with MeOH and purified by RF-HPLC (pH 10) to afford6-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methylthieno[3,2-b]pyridin-7-amine(96 mg, 74%) as a white solid. LC-MS calculated for C₁₇H₂₀O₂N₃S [M+H]⁺m/z: 330.1; found 330.1.

Step 4:3-(3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of6-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methylthieno[3,2-b]pyridin-7-amine(96 mg, 0.13 mmol) in CH₃CN (3.0 mL) was added1,1′-thiocarbonyldiimidazole (210 mg, 1.2 mmol). The resulting mixturewas stirred at 110° C. for 12 h before it was concentrated in vacuo. Thecrude mixture was purified by flash column (MeOH/DCM 5%˜20%) to afford3-(3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one(120 mg, 86%) as a yellow solid. LC-MS calculated for C₁₈H₁₈O₃N₃S [M+H]⁺m/z: 356.1; found 356.1.

Step 5:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of3-(3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one(10.0 mg, 0.0281 mmol) in CH₃CN (1.0 mL) was added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (Selectfluor®) (24.9 mg, 0.0703 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for 2h before it was diluted with MeOH (9 mL). The compound was purified byRF-HPLC (pH=10) to afford3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2′,3′:5,6]pyrido[4,3-d]pyrimidin-2(1H)(3.0 mg, 27%) as a white solid. LC-MS calculated for C₁₈H₁₆F₂N₃O₃S[M+H]⁺ m/z: 392.1; found 392.1. ¹H NMR (500 MHz, DMSO) δ 8.40 (s, 1H),8.15 (d, J=5.6 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H), 7.05 (t, J=8.2 Hz, 1H),4.85 (s, 2H), 3.89 (s, 6H), 3.71 (s, 3H).

Example 393-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:5-{(E)-[(2,6-difluoro-3,5-dimethoxyphenyl)imino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of 4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(1.98 g, 11.3 mmol, prepared as described in Example 1, Step 1),2,6-difluoro-3,5-dimethoxyaniline (2.6 g, 14 mmol) andD-(+)-10-camphorsulfonic acid (Aldrich, cat #21360: 0.72 g, 3.1 mmol) intoluene (200 mL) was heated to reflux with azeotropic removal of watervia a Dean-stark trap for 48 h. The reaction mixture was concentratedand the residue was used in the next step without further purification.LC-MS calculated for C₁₇H₁₇F₂N₄O₂ [M+H]⁺ m/z: 347.1; found 347.1.

Step 2:5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine

The crude product from Step 1 was dissolved in tetrahydrofuran (200 mL)and cooled to 0° C. then LiAlH₄ (0.86 g, 23 mmol) was added. Thereaction mixture was warmed to 50° C. and stirred overnight. Thereaction was quenched by addition of a minimum amount of water at 0° C.then filtered through Celite and washed with THF. The filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluted with 0-5% methanol indichloromethane to afford the desired product (2.00, 51%) as a yellowsolid. LC-MS calculated for C₁₇H₁₉F₂N₄O₂ [M+H]⁺ m/z: 349.1; found 349.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Triphosgene (2.0 g, 6.8 mmol) was added to a solution of the productfrom Step 2 and triethylamine (7.9 mL, 56 mmol) in tetrahydrofuran (160mL) at 0° C. The reaction mixture was stirred at room temperature for 1h, then 1M NaOH (50 mL) was added. After stirring for 30 min at roomtemperature, saturated aqueous solution of NH₄Cl (10 mL) was added. Themixture was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The mixture was used for next stepwithout further purification. LC-MS calculated for C₁₈H₁₇F₂N₄O₃ [M+H]⁺m/z: 375.1; found 375.0.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(2.30 g, 6.14 mmol) in tetrahydrofuran (30 mL) was added NaH (60% inmineral oil, 0.344 g, 8.60 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 30 min then benzenesulfonyl chloride (0.94 mL, 7.4mmol) was added. After stirring at 0° C. for 1 h, the reaction wasquenched with saturated aqueous solution of NH₄Cl then extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine, dried over MgSO₄, then filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluted with ethyl acetate in DCM (0-30%) to afford thedesired product (1.89 g, 68.8%). LC-MS calculated for C₂₄H₂₁F₂N₄O₅S[M+H]⁺ m/z: 515.1; found 515.0.

Step 5:8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

(1) Preparation of LDA solution: To a stirred solution ofN,N-diisopropylamine (0.632 mL, 4.51 mmol) in tetrahydrofuran (10 mL) at−78° C. was added 2.5 M n-butyllithium in hexanes (1.6 mL, 4.0 mmol)dropwise. After a white precipitate formed, the mixture was warmed up to0° C. and stirred for 10 min.

(2) To a stirred solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(1.60 g, 3.11 mmol) in tetrahydrofuran (100 mL) at −78° C. was added thefreshly prepared LDA solution dropwise. After 30 min, a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (1.06 g, 3.26 mmol) intetrahydrofuran (6 mL) was added dropwise. The resulting clear yellowsolution was stirred at −78° C. for 1 h. The reaction mixture wasquenched with saturated aqueous solution of NH₄Cl then extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column with EtOAc in DCM (0-10%) to afford the desired product (1.50g, 81.3%). LC-MS calculated for C₂₄H₂₀BrF₂N₄O₅S [M+H]⁺ m/z: 593.0; found592.9.

Step 6:8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(1.50 g) in tetrahydrofuran (10 mL) was added 5.0 M sodium methoxide inmethanol (1.9 mL, 9.3 mmol). After stirring at room temperature for 1 h,the mixture was diluted with water and adjusted to pH=8 with 1 N HCl,then concentrated to remove THF. The solid was filtered, washed withwater and dried in vacuum to afford the desired product (0.83 g). LC-MScalculated for C₁₈H₁₆BrF₂N₄O₃ [M+H]⁺ m/z: 453.0; found 453.0.

Step 7:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(10.0 mg, 0.0221 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(6.0 mg, 0.029 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (1:1) (2 mg, 0.003 mmol) and potassium carbonate(9.1 mg, 0.066 mmol) in 1,4-dioxane (0.80 mL) and water (0.20 mL) wasdegassed and filled with nitrogen. After stirring at 95° C. for 3 h, thereaction mixture was diluted with MeOH, and filtered. The solution wasused in the next step. LC-MS calculated for C₂₃H₂₃F₂N₄O₄ [M+H]⁺ m/z:457.2; found 457.1.

Step 8:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Palladium on activated carbon (10 wt %, 10 mg) was added to the solutionof product from Step 7 in methanol (5 mL) and the reaction mixture wasstirred at room temperature under a balloon of H₂ for 2 h. The mixturewas filtered and purified by RP-HPLC (pH=2) to afford the desiredproduct. LC-MS calculated for C₂₃H₂₅F₂N₄O₄ [M+H]⁺ m/z: 459.2; found459.1.

Example 403-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a stirred solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(700 mg, 1.36 mmol) in tetrahydrofuran (20 mL) was added freshlyprepared LDA solution (1M in THF, 1.95 mL, 1.4 eq) at −78° C. Themixture was stirred at −78° C. for 30 min then dry CO₂ gas (preparedfrom dry ice by passing through a drying tube) was bubbled into thereaction mixture for 30 min. The reaction was then quenched with 1N HClat −78° C. After warming to room temperature, the reaction mixture wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column: 0 to 5% MeOH/DCM, to givethe desired product (519 mg, 68%). LC-MS calculated for C₂₅H₂₁F₂N₄O₇S[M+H]⁺ m/z: 559.1; found 559.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (762 mg, 1.36 mmol) in tetrahydrofuran (23 mL) was added 1.0 Mpotassium tert-butoxide in THF (6.0 mL, 6.0 mmol). The resulting lightyellow suspension was stirred at room temperature for 30 min at whichtime LC-MS indicated the reaction was complete to the desired product.The reaction was quenched with water then extracted with EtOAc. Theaqueous layer was acidified with 1N HCl and the white precipitate wascollected via filtration and dried to afford the pure product (528 mg,93%) as a white solid. LC-MS calculated for C₁₉H₁₇F₂N₄O₅ [M+H]⁺ m/z:419.1; found 419.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carboxylicacid (207 mg, 0.495 mmol) in N,N-dimethylformamide (15 mL) was addedtriethylamine (210 μL, 1.5 mmol), followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(230 mg, 0.52 mmol). The mixture was stirred for 5 min at roomtemperature then 1-methylpiperazine (160 μL, 1.5 mmol) was added. Afterstirred at room temperature for 30 min, the reaction mixture was dilutedwith MeOH then purified by RP-HPLC (pH=2) to give the desired product(200 mg, 81%) as a white solid. LC-MS calculated for C₂₄H₂₇F₂N₆O₄ [M+H]⁺m/z: 501.2; found 501.1.

Example 413-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylcarbonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 40, Step 3 with morpholine replacing 1-methylpiperazine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₃H₂₄F₂N₅O₅ [M+H]⁺ m/z: 488.2; found:488.2.

Example 423-(2,6-Difluoro-3,5-dimethoxyphenyl)-8-[(4,4-difluoropiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedure analogous to those forExample 40, Step 3 with 4,4-difluoropiperidine hydrochloride replacing1-methylpiperazine. Purified by RP-HPLC (pH=2) to afford the desiredproduct as a white solid. LC-MS calculated for C₂₄H₂₄F₄N₅O₄ [M+H]⁺ m/z:522.2; found: 522.1.

Example 433-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(168.0 mg, 0.4488 mmol) in N,N-dimethylformamide (4 mL) was added asolution of N-bromosuccinimide (88 mg, 0.49 mmol) inN,N-dimethylformamide (0.56 mL) dropwise at 0° C. The resulting solutionwas stirred at room temperature for 2 h. The reaction was quenched withwater and extracted with CH₂Cl₂. The combined organic phase was washedwith brine, dried over Na₂SO₄. The solvents were removed under reducedpressure to afford the desired compound which was used in the next stepwithout further purification. LC-MS calculated for C₁₈H₁₆BrF₂N₄O₃ [M+H]⁺m/z: 453.0; found: 453.1.

Step 2: tert-butyl9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate

To a stirred solution of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(200 mg, 0.4 mmol) in methylene chloride (3 mL) was added di-tert-butylcarbonate (180 mg, 1.0 mmol) and 4-dimethylaminopyridine (10.8 mg, 0.088mmol). The resulting solution was stirred at room temperature for 2 h atwhich time LC-MS analysis showed that the reaction was complete. Thereaction mixture was concentrated and the residue was purified by flashchromatography on a silica gel column eluting with 10% AcOEt in CH₂Cl₂to afford the desired compound (170 mg, 70%). LC-MS calculated forC₂₃H₂₄BrF₂N₄O₅ [M+H]⁺ m/z: 553.1; found: 553.0.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of tert-butyl9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate(35.0 mg, 0.063 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26mg, 0.13 mmol), bis(tri-t-butylphosphine)palladium (6 mg, 0.01 mmol),and N,N-diisopropylethylamine (33 μL, 0.19 mmol) in 1,4-dioxane (1.7 mL)and water (0.2 mL) was degassed then filled with nitrogen. Afterstirring at 120° C. for 2 h, the reaction mixture was filtered andconcentrated to dryness. The residue was dissolved in TFA/CH₂Cl₂ (1:1, 1mL) and stirred at room temperature for 1 h. The reaction mixture wasconcentrated and the residue was dissolved in MeOH and purified byRP-HPLC (pH=2) to afford the desired product. LC-MS calculated forC₂₂H₂₁F₂N₆O₃ [M+H]⁺ m/z: 455.2; found: 455.1.

Example 443-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 39, Steps 1-3, with4-(allylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (preparedaccording to Example 1, Step 1) replacing4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde. LC-MScalculated for C₂₀H₁₉F₂N₄O₃ [M+H]⁺ m/z: 401.1; found: 401.1.

Step 2:1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(0.35 g, 0.89 mmol) in DMF (4 mL) was added sodium hydride ((60%dispersion in mineral oil, 0.053 g, 1.3 mmol) at 0° C. The mixture wasstirred for 20 minutes then benzenesulfonyl chloride (0.14 mL, 1.1 mmol)was added and the reaction was stirred for another 1 h at 0° C. Themixture was diluted with water and the formed precipitate was collectedvia filtration then washed with water and dried to provide the desiredproduct. LC-MS calculated for C₂₆H₂₃F₂N₄O₅S [M+H]⁺ m/z: 541.1; found:541.1.

Step 3.[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]acetaldehyde

To a solution of1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(120 mg, 0.22 mmol) in tert-butyl alcohol (2 mL) was addedN-methylmorpholine N-oxide (28.6 mg, 0.244 mmol) and water (0.70 mL, 39mmol). To this solution was then added aqueous osmium tetraoxide (0.070mL, 0.011 mmol, 4%). Another portion of N-methylmorpholine N-oxide (28.6mg, 0.244 mmol) was added after 3 h. The reaction mixture was stirred atroom temperature for 3 days. The solution was diluted with water,extracted with methylene chloride. The combined organic layers weredried over MgSO₄, filtered then concentrated. The residue was dissolvedin THF (1.7 mL)/water (0.83 mL) and then sodium periodate (0.14 g, 0.66mmol) was added, followed by acetic acid (0.0032 mL, 0.055 mmol) at 0°C. After stirring for 2 h, the reaction mixture was diluted with water,extracted with methylene chloride. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting withEtOAc/CH₂Cl₂ (0 to 20%). LC-MS calculated for C₂₅H₂₁F₂N₄O₆S [M+H]⁺ m/z:543.1; found: 543.1.

Step 4.3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]acetaldehyde(50.0 mg, 0.0922 mmol) in methanol (1.5 mL) was added sodiumtetrahydroborate (7.0 mg, 0.18 mmol). After stirring at room temperaturefor 30 min, the mixture was diluted with methylene chloride then washedwith saturated aqueous solution of NaHCO₃, water, and brine, and thenthe mixture was dried over Na₂SO₄, filtered and concentrated to providethe product which was used in the next step directly. LC-MS calculatedfor C₂₅H₂₃F₂N₄O₆S [M+H]⁺ m/z: 545.1; found: 545.1.

Step 5.3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

6.0 M Potassium hydroxide in water (0.1 mL, 0.6 mmol) was added to asolution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(30.0 mg, 0.0551 mmol) in THF (0.6 mL) and then the mixture was stirredat 70° C. overnight. The product was purified by RP-HPLC (pH=2) toafford the desired product as a white solid. LC-MS calculated forC₁₉H₁₉F₂N₄O₄ [M+H]⁺ m/z: 405.1; found: 405.2. ¹H NMR (400 MHz, DMSO) δ12.03 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.04 (t, J=8.0 Hz, 3H), 6.73(s, 1H), 4.78 (s, 2H), 4.23 (t, J=6.8 Hz, 2H), 3.89 (s, 6H), 3.70 (t,J=6.8 Hz, 2H).

Example 451-Cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:N-[(1E)-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methylene]-2,6-difluoro-3,5-dimethoxyaniline

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (5.00 g,27.7 mmol), 2,6-difluoro-3,5-dimethoxyaniline (6.3 g, 33 mmol) andp-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol) in toluene (300 mL)was heated to reflux with azeotropic removal of water via a Dean-Starktrap. After stirred for overnight, the reaction mixture was concentratedand the residue was used in the next step without further purification.

Step 2:N-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

The crude product from Step 1 was dissolved in tetrahydrofuran (300 mL)and cooled to 0° C. then LiAlH4 (3.6 g, 96 mmol) was added. The reactionmixture was warmed to 50° C. and stirred overnight. The reaction wasthen quenched with a minimum amount of water and diluted with ethylacetate. The mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with methanol indichloromethane (0-5%) to afford the desired product (7.00 g, 71.5%).LC-MS calculated for C₁₆H₁₅ClF₂N₃O₂ [M+H]⁺ m/z: 354.1; found 354.0.

Step 3:N-cyclopropyl-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture ofN-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(0.25 g, 0.71 mmol), cyclopropylamine (0.088 mL, 1.3 mmol), palladiumacetate (16 mg, 0.071 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (44 mg, 0.071 mmol),and cesium carbonate (0.70 g, 2.1 mmol) in 1,4-dioxane (10 mL) wasdegassed then filled with nitrogen. After stirring at 160° C. overnight,the reaction mixture was diluted with ethyl acetate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with MeOH in DCM (0-5%) toafford the desired product (0.17 g, 64%). LC-MS calculated forC₁₉H₂₁F₂N₄O₂ [M+H]⁺ m/z: 375.2; found 375.1.

Step 4:1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Triphosgene (0.20 g, 0.6 mmol) was added to a solution ofN-cyclopropyl-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(0.17 g, 0.44 mmol) and triethylamine (590 μL, 4.2 mmol) intetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 30 min, then 2 N NaOH (2.0 mL) was added. After stirringat room temperature for 1 h, the reaction mixture was extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluting with MeOH in DCM (0-5%) to afford the desiredproduct. LC-MS calculated for C₂₀H₁₉F₂N₄O₃ [M+H]⁺ m/z: 401.1; found401.1. ¹H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.04 (s, 1H), 7.52-7.46(m, 1H), 7.03 (t, J=8.2 Hz, 1H), 6.97-6.93 (m, 1H), 4.66 (s, 2H), 3.88(s, 6H), 3.38-3.28 (m, 1H), 1.13-1.03 (m, 2H), 0.70-0.62 (m, 2H).

Example 463-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with tetrahydro-2H-pyran-4-amine replacing cyclopropylamine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₂H₂₃F₂N₄O₄ [M+H]⁺ m/z: 445.2; found 445.0.¹H NMR (300 MHz, DMSO) δ 11.95 (s, 1H), 8.03 (s, 1H), 7.56-7.49 (m, 1H),7.03 (t, J=8.2 Hz, 1H), 6.45-6.36 (m, 1H), 4.69 (s, 2H), 4.48-4.32 (m,1H), 4.03-3.92 (m, 2H), 3.88 (s, 6H), 3.52-3.37 (m, 2H), 2.82-2.62 (m,2H), 1.94-1.83 (m, 2H).

Example 473-(2,6-difluoro-3,5-dimethoxyphenyl)-1-phenyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with aniline replacing cyclopropylamine. Purified by RP-HPLC(pH=2) to afford the desired product as a white solid. LC-MS calculatedfor C23H19F2N4O3 [M+H]⁺ m/z: 437.1; found 437.1. ¹H NMR (500 MHz, DMSO)δ 11.81 (s, 1H), 8.11 (s, 1H), 7.57-7.51 (m, 3H), 7.50-7.44 (m, 2H),7.13-7.09 (m, 1H), 7.06 (t, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.31-4.27 (m,1H), 3.89 (s, 6H).

Example 481-Cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 37 with1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 45) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.Purified by RP-HPLC (pH=10) to afford the desired product as a whitesolid. LC-MS calculated for C₂₀H₁₉F₂N₄O₄ [M+H]⁺ m/z: 417.1; found 417.0.¹H NMR (300 MHz, DMSO) δ 11.03 (s, 1H), 7.82 (s, 1H), 7.02 (t, J=8.2 Hz,1H), 4.48 (s, 2H), 3.99 (s, 2H), 3.87 (s, 6H), 3.14-3.00 (m, 1H),1.08-0.94 (m, 2H), 0.69-0.58 (m, 2H).

Example 493-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS#958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) andethylamine (10M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL,200 mmol) was heated to 130° C. and stirred overnight. The mixture wascooled to room temperature then concentrated under reduced pressure. Theresidue was treated with 1N HCl (30 mL) and stirred at room temperaturefor 1 h then neutralized with saturated NaHCO₃ aqueous solution. Theprecipitate was collected via filtration then washed with water anddried to provide the desired product (2.9 g, 92%). LC-MS calculated forC₁₀H₁₂N₃O [M+H]⁺ m/z: 190.1; found: 190.1.

Step 2:5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol) and[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid(Aldrich, cat #21360: 2 g, 7 mmol) in xylenes (250 mL) was heated toreflux with azeotropic removal of water using Dean-Stark for 2 days atwhich time LC-MS showed the reaction was complete. The mixture wascooled to room temperature and the solvent was removed under reducedpressure. The residue was dissolved in tetrahydrofuran (500 mL) and then2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was addedslowly and the resulting mixture was stirred at 50° C. for 3 h thencooled to room temperature. The reaction was quenched by addition ofwater, 15% aqueous NaOH and water. The mixture was filtered and washedwith THF. The filtrate was concentrated and the residue was washed withCH₂Cl₂ and then filtered to get the pure product (11 g, 82%). LC-MScalculated for C₁₈H₂₁F₂N₄O₂ [M+H]⁺ m/z: 363.2; found: 363.1.

Step 3:3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL)was added slowly to a mixture of5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine(5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0° C. and then themixture was stirred at room temperature for 6 h. The mixture was cooledto 0° C. and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) wasadded slowly. The reaction mixture was stirred at room temperatureovernight and the formed precipitate was collected via filtration,washed with water, and then dried to provide the first batch of thepurified desired product. The organic layer in the filtrate wasseparated and the aqueous layer was extracted with methylene chloride.The combined organic layer was concentrated and the residue wastriturated with methylene chloride then filtered and dried to provideanother batch of the product (total 5.5 g, 92%). LC-MS calculated forC₁₉H₁₉F₂N₄O₃ [M+H]⁺ m/z: 389.1; found: 389.1.

Step 4:3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

To a mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(3.0 g, 7.7 mmol) in isopropyl alcohol (70 mL, 900 mmol)/water (7 mL,400 mmol) was added pyridinium tribromide (11 g, 31 mmol). Then thereaction mixture was stirred at 40° C. for 3 h. The mixture was cooledto room temperature and then acetic acid (10 mL, 200 mmol) and zinc(5.05 g, 77.2 mmol) were added. The resulting mixture was stirred atroom temperature overnight then filtered. The filtrate was concentratedand the residue was triturated with water (100 mL)/AcCN (10 mL) andstirred for 30 min. The solid was collected via filtration then dried.The solid was then stirred with CH₂Cl₂/MeOH (100 mL/10 mL) for 30 minthen filtered and dried to provide the pure desired product. Thefiltrate was concentrated and the residue was stirred with AcCN/Water(40 mL/5 mL) at 40° C. for 10 min then filtered and dried to provideanother batch of pure product. LC-MS calculated for C₁₉H₁₉F₂N₄O₄ [M+H]⁺m/z: 405.1; found: 405.2. ¹H NMR (500 MHz, DMSO-d₆): δ 1.19 (t, 3H),3.86 (m, 2H), 3.88 (s, 6 H), 3.90 (m, 2H), 4.61 (s, 2H), 7.03(m, 1H),7.83 (s, 1H), 11.01 (s, 1H) ppm.

Example 501-(Cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared by using procedure analogous to thosedescribed for the synthesis of Example 49 with4-(cyclopropylmethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(prepared according to Example 1, Step 1) replacing4-(ethylamino)-1H-pyrrolo[2, 3-b]pyridine-5-carbaldehyde. LC-MScalculated for C₂₁H₂₁F₂N₄O₄ [M+H]⁺ m/z: 431.2; found: 431.1. ¹14 NMR(500 MHz, DMSO) δ 11.03 (s, 1H), 7.85 (s, 1H), 7.04 (t, J=8.1 Hz, 1H),4.62 (s, 2H), 3.19-3.87 (m, 8H), 3.83 (d, J=6.6 Hz, 2H), 1.16-1.07 (m,1H), 0.50-0.43 (m, 2H), 0.31-0.24 (m, 2H).

Example 513-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1-(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

This compound was prepared using procedures analogous to those forExample 39, Steps 1-2, from1-(4-methoxybenzyl)-4-(methylamino)-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde(Prepared by the same method as described in WO 2007/134259). The crudemixture was purified by flash column (MeOH/DCM, 3%˜20%) to afford theaniline as a white solid. LC-MS calculated for C₂₄H₂₆F₂N₅O₃ [M+H]⁺ m/z:470.2; found 470.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 39, Step 3. The product was purified by flash column(EtOAc/hexanes, 30%˜80%) to afford the urea as a white solid. LC-MScalculated for C₂₅H₂₄F₂N₅O₄ [M+H]⁺ m/z: 496.2; found 496.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

A solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(300 mg, 0.6 mmol) in TFA (4.0 mL) was heated to 70° C. for 2 h. Thesolution was cooled to room temperature and concentrated under reducedpressure. The residue was purified by RP-HPLC (pH 2) to afford thedesired product as a white solid. LC-MS calculated for C₁₇H₁₆O₃N₅F₂[M+H]⁺ m/z: 376.1; found 376.1. ¹H NMR (300 MHz, DMSO) δ 13.67 (s, 1H),8.41 (s, 1H), 8.24 (s, 1H), 7.06 (t, J=8.2 Hz, 1H), 4.83 (s, 2H), 3.89(s, 6H), 3.66 (s, 3H).

Example 523-(2,6-Difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(250.0 mg, 0.6661 mmol) in CH₃CN (6.0 mL) at 0° C. was addedN-bromosuccinimide (150 mg, 0.86 mmol). The mixture was stirred for 2 hbefore concentrated under reduced pressure. The residue was purified bycolumn (MeOH/DCM, 3%˜30%) to afford the product (300.0 mg, 99%) as awhite solid. LC-MS calculated for C₁₇H₁₅BrO₃N₅F₂ [M+H]⁺ m/z: 454.0;found 454.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(80.0 mg, 0.176 mmol) in 1,4-dioxane (2.0 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (20.0 mg, 0.0245 mmol). To this solution was added ZnMe₂(0.50 mL, 2.0 M solution in toluene, 1.0 mmol). The resulting mixturewas heated to 100° C. for 1 h before it was diluted with MeOH andpurified by RP-HPLC (pH 2). LC-MS calculated for C₁₈H₁₈O₃N₅F₂ [M+H]⁺m/z: 390.1; found 390.1. ¹H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 7.03 (t,J=9.0 Hz, 1H), 4.78 (s, 2H), 3.88 (s, 6H), 3.55 (s, 3H), 2.67 ppm (s,3H).

Example 533-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidine-9-carbonitrile

To a solution of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(15.0 mg, 0.033 mmol) in DMF (1.0 mL) was added zinc cyanide (12.0 mg,0.099 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (5.0 mg, 0.007 mmol). The resulting mixture washeated to 180° C. for 1 h before it was diluted with MeOH and purifiedby RP-HPLC (pH 2). LC-MS calculated for C₁₈H₁₅O₃N₆F₂ [M+H]⁺ m/z: 401.1;found 401.1.

Example 54[3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile

To a mixture of(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.3 mg,0.0057 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.6 mg, 0.0029mmol),9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(13.0 mg, 0.0286 mmol) in N,N-dimethylformamide (1.0 mL, 13 mmol) underan atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (12 μL,0.086 mmol), followed by zinc difluoride (5.9 mg, 0.057 mmol). Thereaction mixture was stirred at 140° C. for 4.5 h under microwaveconditions. The mixture was diluted with MeOH and purified by RP-HPLC(pH 2) to afford the product. LC-MS calculated for C₁₉H₁₇O₃N₆F₂ [M+H]⁺m/z: 415.1; found 415.1. ¹H NMR (400 MHz, DMSO) δ 13.82 (s, 1H), 8.26(s, 1H), 7.04 (t, J=8.1 Hz, 1H), 4.80 (s, 2H), 4.59 (s, 2H), 3.88 (s,6H), 3.52 (s, 3H).

Example 553-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared from9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-oneand1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridineusing procedures analogous to those for Examples 39, step 7-8. Theresidue was purified by RP-HPLC (pH 2) to afford the product as a whitesolid. LC-MS calculated for C₂₃H₂₇F₂N₆O₃ [M+H]⁺ m/z: 473.2; found 473.2.

Example 563-(2,6-Difluoro-3,5-dimethoxyphenyl)-9-(2-hydroxyethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13.6 mg,0.0881 mmol)9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(20.0 mg, 0.0440 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (5.4 mg, 0.0066 mmol) and potassium carbonate(18.0 mg, 0.13 mmol) in 1,4-dioxane (0.80 mL, 10. mmol)/water (0.20 mL,11 mmol) was heated at 88° C. After 1.5 h, the reaction was quenchedwith water, extracted with DCM, dried over Na₂SO₄ and concentrated underreduced pressure. The crude mixture was purified via flash columnchromatography (MeOH/DCM, 3%˜30%) to afford3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-vinyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one.

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-vinyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(17.0 mg, 0.036 mmol) in THF (1.0 mL) was added BH₃-THF (0.40 mmol). Theresulting mixture was stirred at room temperature for 12 h before it wasquenched with NaOH (2 N, 0.2 mL) and H₂O₂ (0.2 mL). The mixture wasdiluted with MeOH and purified by RP-HPLC (pH 2) to afford the productas a white solid. LC-MS calculated for C₁₉H₂₀F₂N₅O₄ [M+H]⁺ m/z: 420.1;found 420.1.

Example 573-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 51. The residue was purified by RP-HPLC (pH 2) to afford theproduct as a white solid. LC-MS calculated for C₁₈H₁₈O₃N₅F₂ [M+H]⁺ m/z:390.1; found 390.1. ¹H NMR (300 MHz, DMSO) δ 13.71 (s, 1H), 8.29 (s,1H), 8.23 (s, 1H), 7.06 (t, J=8.2 Hz, 1H), 4.83 (s, 2H), 4.19 (q, J=6.8Hz, 2H), 3.89 (s, 6H), 1.32 (t, J=6.8 Hz, 3H).

Example 583-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 44. The residue was purified by RP-HPLC (pH 2) to afford theproduct as a white solid. LC-MS calculated for C₁₈H₁₈O₄N₅F₂ [M+H]⁺ m/z:406.1; found 406.1.

Example 593′-(2,6-Difluoro-3,5-dimethoxyphenyl)-1′-methyl-4′,7′-dihydrospiro[cyclopropane-1,9′-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine]-2′,8′(1′H,3′H)-dione

Step 1.3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(0.10 g, 0.27 mmol) in DMF (0.8 mL) was added sodium hydride (60 wt %dispersion in mineral oil, 0.013 g, 0.32 mmol) at 0° C. and stirred for20 minutes. Then (trimethylsilyl)ethoxymethyl chloride (0.057 mL, 0.32mmol) was added and the reaction mixture was stirred for 1 h at 0° C.The mixture was diluted with ethyl acetate and then washed with water,brine, dried over Na₂SO₄ and concentrated. The product was isolated bychromatography eluted with 0 to 40% EtOAc/CH₂Cl₂. LC-MS calculated forC₂₄H₃₁F₂N₄O₄Si (M+H)⁺ m/z: 505.2; found 505.2.

Step 2.3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Pyridinium tribromide (0.299 g, 0.841 mmol) was added to a mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(0.12 g, 0.24 mmol) in isopropyl alcohol (2 mL)/water (0.12 mL), andthen the reaction mixture was stirred at 50° C. for 2 h. The mixture wascooled to room temperature and then acetic acid (0.9 mL) and zinc (0.157g, 2.40 mmol) were added. The mixture was stirred for 6 h then filteredand the solvent was removed. The residue was diluted with methylenechloride, and then washed with saturated NaHCO₃, water, and brine. Theorganic layer was dried over Na₂SO₄ then filtered and concentrated. Theresidue was purified by chromatography eluted with 0 to 50%EtOAc/CH₂Cl₂. LC-MS calculated for C₂₄H₃₁F₂N₄O₅Si (M+H)⁺ m/z: 521.2;found: 521.1.

Step 3.3′-(2,6-Difluoro-3,5-dimethoxyphenyl)-1′-methyl-4′,7′-dihydrospiro[cyclopropane-1,9′-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine]-2′,8′(1′H,3′H)-dione

Nitrogen was bubbled through a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione(100.0 mg, 0.192 mmol) in DMF (2.0 mL) for 20 minutes then cesiumcarbonate (190 mg, 0.58 mmol) and 1-bromo-2-chloroethane (48 μL, 0.58mmol) were added under nitrogen. After stirred at room temperatureovernight, the mixture was filtered and then the solvent was removedunder reduced pressure. The residue was dissolved in CH₂Cl₂ (0.5 mL) andthen TFA (0.8 mL) was added and the reaction mixture was stirred for 1h. The solvent was removed and the residue was dissolved in methanol (2mL) and then ethylenediamine (0.15 mL) was added and the mixture wasstirred at room temperature for 2 h. The product was purified byprep-HPLC (pH 2). LC-MS calculated for C₂₀H₁₉F₂N₄O₄ (M+H)⁺ m/z: 417.1;found: 417.1. ¹H NMR (500 MHz, DMSO) δ 11.31 (s, 1H), 7.90 (s, 1H), 7.01(t, J=8.1 Hz, 1H), 4.59 (s, 2H), 3.87 (s, 6H), 3.14 (s, 3H), 1.92-1.87(m, 2H), 1.49-1.43 (m, 2H).

Example 607-(2,6-difluoro-3,5-dimethoxyphenyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Step 1.N-[(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

To a solution ofN-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(0.35 g, 0.99 mmol) in DMF (3.0 mL) was added sodium hydride (60 wt %dispersion in mineral oil, 48 mg, 1.19 mmol) at 0° C. The mixture wasstirred for 20 minutes then trimethylsilylethoxymethyl chloride (0.210mL, 1.19 mmol) was added and the reaction mixture was stirred for 1 h at0° C. The mixture was diluted with ethyl acetate and then washed withwater and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was isolated by chromatography eluted with 0to 10% EtOAc/CH₂Cl₂. LC-MS calculated for C₂₂H₂₉ClF₂N₃O₃Si (M+H)⁺ m/z:484.2; found: 484.2.

Step 2.7-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Preparation of potassium ethyl malonate: A 100 mL two-neckedround-bottom flask was charged with diethyl malonate (22.0 mmol), water(20.5 mmol) and ethanol (20 mL), and then the reaction mixture wasstirred at 40° C. A solution of potassium tert-butoxide (2.24 g, 20.0mmol) in ethanol (20 mL) was added dropwise over 30 minutes. Aftercompletion of addition, the reaction mixture was stirred at 40° C. untilconsumption of the starting material. The reaction mixture wasconcentrated then diethyl ether (20 mL) was added. The resulting solidwas collected by filtration, washed sequentially with 1:1 mixture ofdiethyl ether and ethanol, then diethyl ether. The solid was dried togive the potassium salt.

A mixture ofN-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(200.0 mg, 0.4132 mmol), potassium ethyl malonate (140 mg, 0.83 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (5.8 mg, 0.012mmol) and n-allylpalladium chloride dimer (14 mg, 0.037 mmol) inmesitylene (2.0 mL) was evacuated and refilled with nitrogen for 3times. The reaction mixture was stirred at 160° C. overnight. Themixture was cooled to room temperature and filtered then washed withethyl acetate. The filtrate was concentrated. The residue was purifiedby chromatography eluted with 0 to 40% EtOAc/CH₂Cl₂. LC-MS calculatedfor C₂₄H₃₀F₂N₃O₄Si (M+H)⁺ m/z: 490.2; found: 490.2.

Step 3.7-(2,6-Difluoro-3,5-dimethoxyphenyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Trifluoroacetic acid (1.0 mL) was added to a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(60.0 mg, 0.122 mmol) in methylene chloride (1.0 mL). The mixture wasstirred at room temperature for 2 h then concentrated. The residue wasdissolved in methanol (1.0 mL) then ethylenediamine (0.2 mL) was added.The mixture was stirred at room temperature for overnight. The productwas purified by prep-HPLC (pH 2). LC-MS calculated for C₁₈H₁₆F₂N₃O₃(M+H)⁺ m/z: 360.1; found: 360.2. ¹H NMR (500 MHz, DMSO) δ 11.77 (s, 1H),8.17 (s, 1H), 7.53-7.48 (m, 1H), 7.05 (t, J=8.2 Hz, 1H), 6.64-6.60 (m,1H), 4.90 (s, 2H), 4.06 (s, 2H), 3.89 (s, 6H).

Example 617-(2,6-difluoro-3,5-dimethoxyphenyl)-9-methyl-3,6,7,9-tetrahydro-8H-imidazo[4′,5′:5,6]pyrido[4,3-d]pyrimidin-8-one

Step 1:6-bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3Himidazo[4,5-b]pyridine

To a solution of 6-bromo-7-chloro-3H-imidazo[4,5-b]pyridine (560 mg, 2.4mmol, PharmaBlock Inc., Cat #PB02862) in N,N-dimethylformamide (10 mL)was added sodium hydride (60% NaH dispersion in mineral oil, 125 mg,3.13 mmol) portion-wise at 0° C. The resulting mixture was stirred at 0°C. for 30 minutes. Then [β-(Trimethylsilyl)ethoxy]methylchloride (0.51mL, 2.89 mmol) was added and the reaction mixture was stirred for 2 h at0° C. The reaction was quenched with saturated NH₄Cl aqueous solutionthen extracted with ethyl acetate. The organic layer was washed withwater, brine then dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography on a silica gel column eluted with 0 to 10%EtOAc/DCM to afford the desired product (615 mg, 70%) as a yellow oil.LC-MS calculated for C₁₂H₁₈BrClN₃OSi [M+H]⁺ m/z: 362.0; found: 362.0.

Step 2:7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl)-6-vinyl-3H-imidazo[4,5-b]pyridine

A solution of6-bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine(615 mg, 1.70 mmol),4-methyl-2,6-dioxo-8-vinyltetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide(326 mg, 1.78 mmol), potassium carbonate (470 mg, 3.4 mmol) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(Aldrich, Cat #678740; 36 mg, 0.05 mmol) in 1,4-dioxane (9 mL, 100 mmol)and water (1 mL, 60 mmol) was evacuated then filled with nitrogen forthree times. The resulting mixture was heated to 95° C. and stirred for5 h, at which time LC-MS indicated the reaction was complete. Themixture was cooled to room temperature, diluted with EtOAc then washedwith water and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography on a silica gelcolumn eluted with 0 to 10% EtOAc/DCM to afford the desired product (454mg, 86%) as a yellow oil. LC-MS calculated for C₁₄H₂₁ClN₃OSi [M+H]⁺ m/z:310.1; found: 310.0.

Step 3:7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine-6-carbaldehyde

To a solution of7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-6-vinyl-3H-imidazo[4,5-b]pyridine(454 mg, 1.46 mmol) in tert-butyl alcohol (10 mL, 100 mmol) and water (2mL, 100 mmol) was added N-methylmorpholine N-oxide (257 mg, 2.20 mmol),followed by Osmium tetraoxide (4 wt % in water, 0.46 mL, 0.073 mmol).The reaction mixture was stirred at room temperature for overnight. Themixture was then diluted with water and extracted with EtOAc. Theorganic layer was washed with brine then dried over Na₂SO₄ andconcentrated. The residue was dissolved in tetrahydrofuran (11 mL, 140mmol) and water (5.5 mL, 3.0E2 mmol) then cooled to 0° C. To thesolution was added sodium periodate (940 mg, 4.4 mmol) and acetic acid(21 μL, 0.37 mmol). After stirred at 0° C. for 2 h, the reaction mixturewas diluted with water then extracted with EtOAc. The organic layer waswashed with brine then dried over Na₂SO₄ and concentrated. The residuewas purified by chromatography on a silica gel column eluted with 0 to20% EtOAc/DCM to afford the desired product (290 mg, 63%) as a whitesolid. LC-MS calculated for C₁₃H₁₉ClN₃O₂Si [M+H]⁺ m/z: 312.1; found:312.0.

Step 4: 7-(methylamino)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde

To a solution of7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine-6-carbaldehyde(225 mg, 0.722 mmol) in 2-methoxyethanol (2 mL) was added methylamine(33 wt % in EtOH, 2 mL, 16 mmol). The mixture was stirred at 110° C. ina sealed tube overnight. The mixture was concentrated and the residuewas dissolved in 10 mL 0.5 N HCl and stirred at room temperature for 1h. The mixture was neutralized with saturated NaHCO₃ aqueous solution.The resulting white precipitate was collected via filtration then dried.The above solid was dissolved in 3 mL DCM and 3 mL TFA was added. Theresulting clear solution was stirred at room temperature for 1 h. Thereaction mixture was concentrated then dried in vacuo. The crude productwas used in the next step without further purification. LC-MS calculatedfor C₈H₉N₄O [M+H]⁺ m/z: 177.1; found: 177.1.

Step 5:6-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine

A mixture of 7-(methylamino)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde(100 mg, 0.6 mmol), 2,6-difluoro-3,5-dimethoxyaniline (160 mg, 0.85mmol) and D-(+)-10-camphorsulfonic acid (40 mg, 0.2 mmol) in toluene (20mL, 200 mmol) was heated to reflux with azotropic removal of water witha Dean-Stark trap. The mixture was refluxed for 24 h then cooled to roomtemperature and concentrated. The residue was dissolved intetrahydrofuran (15 mL, 180 mmol) and cooled to 0° C. then lithiumtetrahydroaluminate (75 mg, 2.0 mmol) was added portion-wise. Thereaction mixture was warmed to 45° C. and stirred for 1 h. The reactionwas quenched by addition of 0.1 mL of water then 0.1 mL of 15% NaOHsolution followed by 0.3 mL of water. The mixture was stirred for 10 minthen filtered. The filtrate was concentrated and the residue waspurified by column eluted with 0 to 10% MeOH/DCM to afford the desiredproduct (155 mg, 80%) as a yellow solid. LC-MS calculated forC₁₆H₁₈F₂N₅O₂ [M+H]⁺ m/z: 350.1; found: 350.0.

Step 6:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-methyl-3,6,7,9-tetrahydro-8H-imidazo[4′,5′:5,6]pyrido[4,3-d]pyrimidin-8-one

To the solution of6-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-Nmethyl-3H-imidazo[4,5-b]pyridin-7-amine(155 mg, 0.44 mmol) in tetrahydrofuran (5 mL, 60 mmol) was addedtriethylamine (0.31 mL, 2.2 mmol), followed by triphosgene (140 mg, 0.49mmol). The resulting yellow suspension was stirred at room temperaturefor 1 h then 5 mL of 1N NaOH aqueous solution was added. After stirredat room temperature for 30 min, the mixture was diluted with EtOAc. Theorganic layer was washed with water, brine then dried over Na₂SO₄ andconcentrated. The residue was dissolved in MeOH and purified by prepHPLC (pH 2, ACN/water) to give the desired product as a white solid.LC-MS calculated for C₁₇H₁₆F₂N₅O₃ [M+H]⁺ m/z: 376.1; found: 376.1. ¹HNMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.10 (s, 1H), 7.05 (t, J=8.2 Hz,1H), 4.83 (s, 2H), 3.89 (s, 6H), 3.85 (s, 3H).

Example 623-(2,6-difluoro-3,5-dimethoxyphenyl)-4,7-dihydropyrazolo[4′,3′:5,6]pyrido[3,4-e][1,3]oxazin-2(3H)-one

Step 1:4-chloro-5-(chloromethyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine

To a stirred solution of[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol(2.70 g, 8.9 mmol) (Lakestar Tech: Lot #123-017-22) in methylenechloride (30 mL, 500 mmol) were added N,N-diisopropylethylamine (3.10mL, 17.8 mmol) and methanesulfonyl chloride (820 μL, 11 mmol)sequentially at 0° C. After 15 minutes, the reaction mixture was warmedup to room temperature. After another 2 hours, the reaction was quenchedwith saturated aq. NaHCO₃, then extracted with methylene chloride. Thecombined organic layers were dried over MgSO₄, and then concentrated.The residue (2.50 g) was used directly in the next step without furtherpurification. LC-MS calculated for C₁₅H₁₄Cl₂N₃O (M+H)⁺: m/z=322.1;Found: 322.1.

Step 2:N-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

A stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (0.88 g, 4.6 mmol)and4-chloro-5-(chloromethyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine(1.00 g, 3.10 mmol) in N,N-diisopropylethylamine (15 mL) was heated to90° C. After 8 hours, the volatiles were removed under reduced pressureand the residue was purified on flash column (eluting with 0-45% EtOAcin hexanes) to afford the desired product as a white solid (1.02 g,71%). LC-MS calculated for C₂₃H₂₂ClF₂N₄O₃ (M+H)⁺: m/z=475.1; Found:475.1.

Step 3:N-{[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

To a stirred solution of 2-propen-1-ol (43 μL, 0.63 mmol) inN,N-dimethylformamide (9 mL, 100 mmol) was added sodium hydride (60 wt %in mineral oil, 34 mg, 0.84 mmol) at 0° C. After 15 minutes,N-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(200 mg, 0.4 mmol) was added and the resulted mixture was heated to 100°C. After stirred at 100° C. for 30 minutes, the reaction mixture wascooled to room temperature and quenched with saturated aq. NH₄Cl, thenextracted with methylene chloride. The combined organic layers weredried over MgSO₄, and then concentrated. The residue (0.2 g, 96%) wasused directly in the next step without further purification. LC-MScalculated for C₂₆H₂₇F₂N₄O₄ (M+H)⁺: m/z=497.2; Found: 497.1

Step 4:{[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(2,6-difluoro-3,5-dimethoxyphenyl)carbamicchloride

To a stirred solution ofN-{[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(150 mg, 0.30 mmol) in THF (6 mL) were added triethylamine (84.2 μL,0.604 mmol) and triphosgene (134 mg, 0.453 mmol) sequentially at roomtemperature. After 3 hours, the reaction mixture was quenched withsaturated aq. NH₄Cl, then extracted with methylene chloride. Thecombined organic layers were dried over MgSO₄, and then concentrated.The residue (0.16 g, 95%) was used directly in the next step withoutfurther purification. LC-MS calculated for C₂₇H₂₅ClF₂N₄O₅ (M+H)⁺:m/z=559.2; Found: 559.2.

Step 5:3-(2,6-difluoro-3,5-dimethoxyphenyl)-4,7-dihydropyrazolo[4′,3′:5,6]pyrido[3,4-e][1,3]oxazin-2(3H)-one

To a stirred solution of crude{[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(2,6-difluoro-3,5-dimethoxyphenyl)carbamicchloride (0.16 g, 0.287 mmol) in THF (0.5 mL)/1-propanol (3 mL, 40 mmol)was added rhodium chloride trihydrate (7.95 mg, 0.0302 mmol). Themixture was then warmed up to 90° C. After 2 hours, the reaction wasquenched with saturated aq. NH₄Cl, then extracted with methylenechloride. The combined organic layers were dried over MgSO₄, and thenconcentrated. The residue was dissolved in trifluoroacetic acid (2 mL,20 mmol) and was heated to 75° C. for 1 hour. The volatiles were thenremoved under reduced pressure and the residue was purified on RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 60 mL/min) to give the desiredproduct (50 mg, 46%) as its TFA salt. LC-MS calculated for C₁₆H₁₃F₂N₄O₄(M+H)⁺: m/z=363.1; Found: 363.1; ¹H NMR (500 MHz, DMSO-d₆): δ 8.41(s,1H), 8.26 (s, 1 H), 7.14 (t, J=10.0 Hz, 1 H), 4.99 (s, 2 H), 3.92 (s, 6H) ppm.

Example 633-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1: N-(2-fluoro-3,5-dimethoxyphenyl)acetamide

To a solution of N-(3,5-dimethoxyphenyl)acetamide (14.8 g, 75.8 mmol) inacetonitrile (200 mL) was added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (Alfa Aesar, cat #L17003: 29 g, 81 mmol). Theresulting suspension was stirred at room temperature overnight thenconcentrated under reduced pressure. The residue was dissolved in ethylacetate (AcOEt) then washed with saturated NaHCO₃ aqueous solution andbrine. The organic layer was dried over Na₂SO₄ then filtered andconcentrated. The residue was purified by chromatography eluted with 0to 50% AcOEt in hexanes to give the desired product (7.8 g, 48%). LC-MScalculated for C₁₀H₁₃FNO₃ (M+H)⁺ m/z: 214.1; found 214.0.

Step 2: N-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)acetamide

To a solution of N-(2-fluoro-3,5-dimethoxyphenyl)acetamide (3.50 g, 16.4mmol) in acetonitrile (40 mL) was added sulfuryl chloride (1.3 mL, 16mmol) dropwise at 0° C. The resulting yellow solution was warmed to roomtemperature and stirred for 30 min. Then the reaction was quenched bydropwise addition of saturated NaHCO₃ solution (25 mL). The precipitatewas collected via filtration then washed with water, and dried to affordthe desired product (3.0 g, 77%). LC-MS calculated for C₁₀H₁₂ClFNO₃(M+H)⁺ m/z: 248.0; found 248.0.

Step 3: 2-chloro-6-fluoro-3,5-dimethoxyaniline

To a solution of N-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)acetamide (3.0g, 12 mmol) in ethanol (120 mL) was added 2.0 M potassium hydroxide inwater (60 mL). The resulting solution was refluxed overnight then cooledto room temperature and concentrated to remove ethanol. The precipitatewas collected via filtration then washed with water and hexanes, thendried to give the product (1.44 g, 58%). LC-MS calculated forC₈H₁₀ClFNO₂ (M+H)⁺ m/z: 206.0; found 206.1.

Step 4:5-{[(2-chloro-6-fluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(Example 49, Step 1: 1.6 g, 8.3 mmol),2-chloro-6-fluoro-3,5-dimethoxyaniline (1.7 g, 8.3 mmol) and[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid(Aldrich, cat #21360: 0.6 g, 2 mmol) in toluene (200 mL, 2000 mmol) washeated to reflux with azotropic removal of water using a Dean-Stark trapfor 4 days. The reaction mixture was cooled to room temperature andconcentrated. The residue was dissolved in tetrahydrofuran (40 mL) andthen lithium tetrahydroaluminate (0.78 g, 21 mmol) was added dropwise.The mixture was stirred at 50° C. for 3 h then cooled to roomtemperature. The reaction was quenched by addition of water (0.8 mL),15% aqueous NaOH (0.8 mL) then water (2.4 mL). The mixture was filteredand washed with THF. The filtrate was concentrated and the residue waspurified by chromatography eluted with 0 to 5% MeOH in CH₂Cl₂ to givethe desired product (1.1 g, 35%). LC-MS calculated for C₁₈H₂₁ClFN₄O₂(M+H)⁺ m/z: 379.1; found 379.1.

Step 5:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a mixture of5-{[(2-chloro-6-fluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine(1.55 g, 4.09 mmol) in tetrahydrofuran (30 mL) at 0° C. was addedtriethylamine (2.8 mL, 20 mmol), followed by a solution of triphosgene(1.8 g, 6.1 mmol) in tetrahydrofuran (8 mL). The resulting mixture wasstirred at room temperature for 3 h then cooled to 0° C. and then 1.0 Msodium hydroxide in water (30 mL) was added slowly. After stirring atroom temperature overnight, the reaction mixture was then extracted withCH₂Cl₂. The organic layer was washed with brine then dried over Na₂SO₄and concentrated. The residue was purified by chromatography eluted with0 to 5% MeOH in CH₂Cl₂ to give the desired product (1.1 g, 66%). LC-MScalculated for C₁₉H₁₉ClFN₄O₃ (M+H)⁺ m/z: 405.1; found: 405.1.

Step 6:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

To a mixture of3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(1.14 g, 2.82 mmol) in isopropyl alcohol (10 mL, 100 mmol) and water(0.8 mL, 40 mmol) was added pyridinium tribromide (3.5 g, 9.8 mmol). Theresulting mixture was stirred at 30° C. overnight then cooled to roomtemperature and acetic acid (10 mL, 200 mmol) and zinc (1.84 g, 28.2mmol) were added. After stirring at room temperature for 2 h, themixture was filtered and the filtrate was concentrated. The residue wastitrated with water and the precipitate was collected via filtrationthen washed with water. The solid was purified by chromatography elutedwith 0 to 5% MeOH in CH₂Cl₂ to give the desired product. LC-MScalculated for C₁₉H₁₉ClFN₄O₄ (M+H)⁺ m/z: 421.1; found: 421.0. ¹H NMR(500 MHz, DMSO) δ 11.02 (s, 1H), 7.83 (s, 1H), 7.01 (d, J=7.7 Hz, 1H),4.56 (s, 2H), 3.94-3.85 (m, 10 H), 1.19 (t, J=7.0 Hz, 3H).

Example 641-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with cyclobutylamine replacing cyclopropylamine. LC-MScalculated for C₂₁H₂₁F₂N₄O₃ (M+H)⁺ m/z: 415.2; found: 415.1.

Step 2:1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 63, Step 6 with1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onereplacing3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₁H₂₁F₂N₄O₄ (M+H)⁺ m/z: 431.2; found: 431.1. ¹HNMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.86 (s, 1H), 7.02 (t, J=8.2 Hz,1H), 4.53 (s, 2H), 4.51-4.42 (m, 1H), 3.88 (s, 6H), 3.80 (s, 2H),2.64-2.53 (m, 2H), 2.32-2.22 (m, 2H), 1.77-1.64 (m, 2H).

Example 653-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 1-(3-fluorophenyl)methanamine replacingcyclopropylamine. LC-MS calculated for C₂₄H₂₀F₃N₄O₃ (M+H)⁺ m/z: 469.1;found: 469.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 63, Step 6 with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onereplacing3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₄H₂₀F₃N₄O₄ (M+H)⁺ m/z: 485.1; found: 485.0. ¹HNMR (500 MHz, DMSO) δ 10.99 (s, 1H), 7.89 (s, 1H), 7.44-7.37 (m, 1H),7.12-6.96 (m, 4H), 5.18 (s, 2H), 4.77 (s, 2H), 3.88 (s, 6H), 3.41 (s,2H).

Example 667′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′,7′-dihydrospiro[cyclopropane-1,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

Nitrogen was bubbled through a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(40 mg, 0.082 mmol) in N,N-dimethylformamide (0.85 mL, 11 mmol) for 20min and then cesium carbonate (80 mg, 0.24 mmol) and1-bromo-2-chloro-ethane (20.3 μL, 0.245 mmol) were added under nitrogen.After stirred at room temperature overnight, the reaction mixture wasfiltered and then concentrated. The residue was dissolved in CH₂Cl₂ (1mL) and then TFA (1 mL) was added. After stirred at room temperature for1 h, the mixture was concentrated and the residue was dissolved inmethanol (2 mL) and then ethylene diamine (0.15 mL) was added. Themixture was stirred at room temperature for 2 h. The product waspurified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₀H₁₈F₂N₃O₃ (M+H)⁺ m/z: 386.1; found:386.1.

Example 677-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound prepared using procedures analogous to those for Example66 with methyl iodide replacing 1-bromo-2-chloroethane. The product waspurified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₀H₂₀F₂N₃O₃ (M+H)⁺ m/z: 388.1; found:388.0. ¹H NMR (500 MHz, DMSO) δ 11.82 (s, 1H), 8.12 (s, 1H), 7.56-7.46(m, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.73-6.70 (m, 1H), 4.90 (s, 2H), 3.90(s, 6H), 1.72 (s, 6H).

Example 681-(4-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:1-(4-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 4-chloro-2-fluoroaniline replacing cyclopropylamine.LC-MS calculated for C₂₃H₁₇ClF₃N₄O₃ [M+H]⁺ m/z: 489.1; found 489.0.

Step 2:1-(4-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 63, Step 6 with1-(4-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onereplacing3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₃H₁₇ClF₃N₄O₄ (M+H)⁺ m/z: 505.1; found: 505.0. ¹HNMR (300 MHz, DMSO) δ 11.03 (s, 1H), 7.95 (s, 1H), 7.73-7.62 (m, 2H),7.50-7.41 (m, 1H), 7.06 (t, J=8.2 Hz, 1H), 4.93 (d, J=14.0 Hz, 1H), 4.76(d, J=14.0 Hz, 1H), 3.88 (s, 6H), 2.58-2.34 (m, 2H).

Example 693-(2,6-difluoro-3,5-dimethoxyphenyl)-9-[4-(4-ethylpiperazin-1-yl)phenyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(30.0 mg, 0.066 mmol) and1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine(31.0 mg, 0.099 mmol) in 1,4-dioxane (0.75 mL) and water (0.25 mL) wereadded potassium carbonate (36.0 mg, 0.26 mmol) andtetrakis(triphenylphosphine)palladium(0) (7.6 mg, 0.0066 mmol). Theresulting mixture was heated to 100° C. for 12 h before it was dilutedwith MeOH and purified by RP-HPLC (pH 2). LC-MS calculated forC₂₉H₃₂F₂N₇O₃ [M+H]⁺ m/z: 564.3; found 564.3. ¹H NMR (300 MHz, DMSO) δ13.8 (s, 1H), 8.27 (s, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.13 (d, J=9.0 Hz,2H), 7.03 (t, J=6.0 Hz, 1H), 4.82 (s, 2H), 3.98 (d, J=9.0 Hz, 2H), 3.88(s, 6H), 3.59 (d, J=9.0 Hz, 2H), 3.22-2.98 (m, 6H), 2.78 (s, 3H), 1.24(t, J=6.0 Hz, 3H).

Example 703-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 39, Step 4: 885 mg, 1.72 mmol) in tetrahydrofuran (20 mL)cooled to −78° C. was added a freshly prepared lithium diisopropylamide(LDA) solution (1 M in THF, 2.6 mL). The resulting yellow suspension wasstirred at −78° C. for 30 min then N,N-dimethylformamide (2 mL) wasadded. The mixture was stirred at 78° C. for 1 h then quenched with 1NHCl. The reaction mixture was then warmed to room temperature andextracted with EtOAc. The organic layer was washed with water, brinethen dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography on a silica gel column eluted with 0 to 10% EtOAcin DCM to afford the desired product (730 mg, 78%) as a white solid.LC-MS calculated for C₂₅H₂₁F₂N₄O₆S [M+H]⁺ m/z: 543.1; found 543.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of sodium triacetoxyborohydride (680 mg, 3.2 mmol) intrifluoroacetic acid (2.1 mL, 28 mmol) cooled to 0° C. was added 3 mL ofdichloromethane (DCM) then 1-ethylpiperazine (580 μL, 4.6 mmol) wasadded to give a yellow solution. Then a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(500 mg, 0.92 mmol) in DCM (10 mL) was dropwise over 5 min. The mixturewas stirred at 0° C. for 2 h then warmed to room temperature and stirredfor overnight. The mixture was poured into saturated NaHCO₃ thenextracted with DCM. The organic layer was then washed with water, brineand dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography on a silica gel column eluted with 0 to 10% MeOH inDCM to afford the desired product (590 mg, 100%) as a white solid. LC-MScalculated for C₃₁H₃₅F₂N₆O₅S [M+H]⁺ m/z: 641.2; found 641.2.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(590 mg, 0.92 mmol) in 25 mL of THF was added potassium tert-butoxide (1M in THF, 4.6 mL). The mixture was stirred at room temperature for 1 hthen the reaction was quenched with saturated NH₄Cl solution andextracted with EtOAc. The organic layer was washed with water, brinethen dried over Na₂SO₄ and concentrated. The residue was purified byprep HPLC (pH=2, ACN/H₂O) to give the desired product as a white solid.LC-MS calculated for C₂₅H₃₁F₂N₆O₃ [M+H]⁺ m/z: 501.2; found 501.2. ¹H NMR(500 MHz, DMSO) δ 12.01 (s, 1H), 8.00 (s, 1H), 7.04 (t, J=8.1 Hz, 1H),6.77 (s, 1H), 4.77 (s, 2H), 3.89 (s, 8H), 3.63 (s, 3H), 3.49 (br, 2H),3.21-2.91 (m, 6H), 2.57 (br, 2H), 1.19 (t, J=7.3 Hz, 3H).

Example 713-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(Z)-2-ethoxyvinyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A flask containing a mixture of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 39, Step 5: 120 mg, 0.20 mmol),2-[(Z)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Synthonix, Cat #E2791: 79 mg, 0.40 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (Aldrich, cat #379670: 20 mg, 0.02 mmol) andpotassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane (5 mL, 60 mmol)and water (0.5 mL, 30 mmol) was evacuated then filled with nitrogenthree times. The reaction mixture was stirred at 95° C. for 1 h thencooled to room temperature and concentrated. The residue was purified byflash chromatography on a silica gel column eluted with 0 to 20% EtOAcin hexanes to afford the desired product (106 mg, 91%). LC-MS calculatedfor C₂₈H₂₇F₂N₄O₆S [M+H]⁺ m/z: 585.2; found 585.1.

Step 2:[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]acetaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(Z)-2-ethoxyvinyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(97 mg, 0.16 mmol) in tetrahydrofuran (10 mL, 100 mmol) was added 1.0 Mhydrogen chloride in water (1.6 mL, 1.6 mmol). The mixture was stirredat 60° C. for 2 h then cooled to room temperature and neutralized withsaturated NaHCO₃ solution. The mixture was extracted with EtOAc. Theorganic layer was washed with water, brine then dried over Na₂SO₄ andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₂₆H₂₃F₂N₄O₆S [M+H]⁺ m/z: 557.1;found 557.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]acetaldehyde(30 mg, 0.054 mmol) in methylene chloride (2 mL) were added1-ethylpiperazine (21 μL, 0.16 mmol) and acetic acid (100 μL). Theresulting yellow solution was stirred at room temperature for 2 h thensodium triacetoxyborohydride (35 mg, 0.16 mmol) was added and thereaction mixture was stirred at room temperature overnight. The mixturewas neutralized with saturated Na₂CO₃ then extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, thenconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₃₂H₃₇F₂N₆O₅S [M+H]⁺ m/z: 655.3;found 655.2.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from step 3 was dissolved in tetrahydrofuran (3 mL)then 1.0 M potassium tert-butoxide in THF (0.20 mL, 0.20 mmol) wasadded. The resulting yellow suspension was stirred at room temperaturefor 30 min then diluted with MeOH and purified by prep HPLC (pH 2,ACN/H₂O) to give the desired product as a white solid. LC-MS calculatedfor C₂₆H₃₃F₂N₆O₃ [M+H]⁺ m/z: 515.3; found 515.2. ¹H NMR (500 MHz, DMSO)δ 11.43 (s, 1H), 7.91 (s, 1H), 7.00 (t, J=8.2 Hz, 1H), 6.57 (s, 1H),4.74 (s, 2H), 3.89 (s, 6H), 3.65 (s, 3H), 3.18 (br, 4H), 3.07 (q, J=7.3Hz, 2H), 3.02-2.93 (m, 4H), 2.88 (br, 4H), 1.22 (t, J=7.3 Hz, 3H).

Example 723-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[3-(4-ethylpiperazin-1-yl)propyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-hydroxyprop-1-yn-1-yl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A flask containing a mixture of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(40 mg, 0.088 mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg,0.009 mmol) and copper(I) iodide (3 mg, 0.02 mmol) inN,N-dimethylformamide (2 mL, 20 mmol) was evacuated then filled withnitrogen. Then 2-propyn-1-ol (26 μL, 0.44 mmol) andN,N-diisopropylethylamine (77 μL, 0.44 mmol) were added. The resultingsolution was heated to 80° C. and stirred for 1 h. The mixture wascooled to room temperature and filtered then purified by prep HPLC (pH2, ACN/H₂O) to give the desired product as a yellow solid. LC-MScalculated for C₂₁H₁₉F₂N₄O₄ [M+H]⁺ m/z: 429.1; found 429.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-hydroxypropyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from step 1 was dissolved in tetrahydrofuran (3 mL, 60 mmol)and methanol (3 mL, 100 mmol) then palladium (10 wt % on carbon, 20 mg)was added. The mixture was stirred under a balloon of hydrogen for 2 hat room temperature then filtered through celite and concentrated togive the crude product, which was used in the next step without furtherpurification. LC-MS calculated for C₂₁H₂₃F₂N₄O₄ [M+H]⁺ m/z: 433.2; found433.2.

Step 3:3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]propanal

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-hydroxypropyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(40. mg, 0.092 mmol) in methylene chloride (5 mL, 80 mmol) was addedDess-Martin periodinane (59 mg, 0.14 mmol). The mixture was stirred atroom temperature for 2 h then the reaction was quenched with saturatedNaHCO₃ solution and extracted with EtOAc. The organic layer was washedwith water, brine then dried over Na₂SO₄ and concentrated. The residuewas used in the next step without further purification. LC-MS calculatedfor C₂₁H₂₁F₂N₄O₄ [M+H]⁺ m/z: 431.2; found 431.1.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[3-(4-ethylpiperazin-1-yl)propyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from step 3 was dissolved in methanol (10 mL) then1-ethylpiperazine (59 μL, 0.46 mmol) and acetic acid (100 μL, 2 mmol)were added. The mixture was stirred at room temperature for 1 h thensodium cyanoborohydride (29 mg, 0.46 mmol) was added. The reactionmixture was stirred at room temperature overnight then the reaction wasquenched with saturated Na₂CO₃ solution and extracted with EtOAc. Theorganic layer was washed with water, brine, then dried over Na₂SO₄ andconcentrated. The residue was dissolved in MeOH then purified by prepHPLC (pH 2, ACN/H₂O) to give the desired product as a white solid. LC-MScalculated for C₂₇H₃₅F₂N₆O₃ [M+H]⁺ m/z: 529.3; found 529.3. ¹H NMR (500MHz, DMSO) δ 11.37 (s, 1H), 7.89 (s, 1H), 7.00 (t, J=8.2 Hz, 1H), 6.49(s, 1H), 4.73 (s, 2H), 3.89 (s, 6H), 3.64 (s, 3H), 3.09 (br, 4H),3.03-2.94 (m, 2H), 2.87 (br, 4H), 2.80 (t, J=7.4 Hz, 2H), 2.73-2.64 (m,2H), 2.02-1.92 (m, 2H), 1.19 (t, J=7.3 Hz, 3H).

Example 733-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(1-ethylpiperidin-4-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: {[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}(iodo)zinc

To a slurry of zinc (255 mg, 3.90 mmol) and celite P65 (50 mg) inN,N-dimethylformamide (0.6 mL, 8 mmol) was added dropwise a 7:5 V/Vmixture (81 μL) of chlorotrimethylsilane:1,2-dibromoethane over fiveminutes. The slurry was stirred at 15 min at room temperature then asolution of tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (preparedusing reported procedures as described in WO 2007/030366: 976 mg, 3.00mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) was added dropwise.After completion of addition, the reaction mixture was heated at 65° C.for 5 min then cooled to room temperature and stirred for 30 min. Themixture was filtered and the filtrate was used directly in the nextstep.

Step 2: tert-butyl4-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperidine-1-carboxylate

A flask containing a mixture of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(163 mg, 0.275 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (22 mg, 0.027 mmol) and copper(I) iodide (16mg, 0.082 mmol) in N,N-dimethylformamide (5 mL) was evacuated thenfilled with nitrogen. The solution from step 1 (0.82 mL) was added thenthe reaction mixture was evacuated again and filled with nitrogen. Theresulting mixture was heated to 85° C., and stirred for overnight. Themixture was cooled to room temperature then filtered through celite andwashed with EtOAc. The filtrate was then washed with water and brine.The organic layer was dried over Na₂SO₄ and concentrated. The residuewas purified by flash chromatography on a silica gel column eluted with0 to 30% EtOAc in DCM to afford the desired product (148 mg, 76%) as alight yellow solid. LC-MS calculated for C₃₅H₄₀F₂N₅O₇S [M+H]⁺ m/z:712.3; found 712.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(piperidin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of tert-butyl4-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperidine-1-carboxylate(140 mg, 0.20 mmol) in tetrahydrofuran (5 mL, 60 mmol) was added 1.0 Mpotassium tert-butoxide in THF (1.0 mL). The mixture was stirred at roomtemperature for 1 h. The reaction was quenched with saturated NH₄Clsolution then extracted with EtOAc. The organic layer was washed withwater, brine and dried over Na₂SO₄ then concentrated. The residue wasdissolved in 2 mL of DCM then 2 mL of TFA was added. The resultingmixture was stirred at room temperature for 1 h and concentrated. Theresidue was dissolved in EtOAc then washed with saturated NaHCO₃solution. The organic layer was washed with water, brine and dried overNa₂SO₄ then concentrated to give the desired product as a yellow solid,which was used in the next step without further purification. LC-MScalculated for C₂₄H₂₈F₂N₅O₃ [M+H]⁺ m/z: 472.2; found 472.1.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(1-ethylpiperidin-4-yl)methy]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a stirred solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(piperidin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(17 mg, 0.035 mmol) in MeOH (2 mL) and THF (2 mL) was added 5.0 Macetaldehyde in THF (35 μL). The mixture was stirred at room temperaturefor 30 min then sodium cyanoborohydride (11 mg, 0.18 mmol) was added.The resulting mixture was stirred at room temperature for 1 h thenpurified by prep HPLC (pH 2, ACN/H₂O) to give the desired product as awhite solid. LC-MS calculated for C₂₆H₃₂F₂N₅O₃ [M+H]⁺ m/z: 500.2; found500.2.

Example 743-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:N-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture ofN-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(prepared as described in Example 45, Step 1-2: 100. mg, 0.283 mmol),(1R,2R)-2-(benzyloxy)cyclopentanamine (Aldrich, Cat #671533: 81.1 mg,0.424 mmol), palladium acetate (6 mg, 0.03 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 0.03 mmol),and cesium carbonate (280 mg, 0.85 mmol) in 1,4-dioxane (3 mL, 40 mmol)was evacuated then filled with nitrogen. The mixture was heated to 160°C. and stirred for overnight. After cooled to room temperature, themixture was diluted with EtOAc and filtered then concentrated underreduced pressure. The residue was purified by flash chromatographyeluted with 0 to 5% MeOH in DCM to give the desired product (63 mg, 44%)as a yellow solid. LC-MS calculated for C₂₈H₃₁F₂N₄O₃ [M+H]⁺ m/z: 509.2;found 509.3.

Step 2:1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of the product from Step 1 in tetrahydrofuran (3 mL, 40mmol) was added triethylamine (90 μL, 0.65 mmol) and triphosgene (56 mg,0.19 mmol). The resulting yellow suspension was stirred at roomtemperature for 1 h then 3 mL of 1 N NaOH was added. The mixture wasstirred at room temperature for another 1 h then diluted with EtOAc. Theorganic layer was washed with water, brine, then dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography eluted with 0 to 5% MeOH in DCM to give the desiredproduct as a yellow solid. LC-MS calculated for C₂₉H₂₉F₂N₄O₄ [M+H]⁺ m/z:535.2; found 535.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of the product from Step 2 in methanol (5 mL) andtetrahydrofuran (5 mL) was added palladium (10 wt % on activated carbon,20 mg) and a few drops of concentrated HCl. The mixture was stirredunder a balloon of hydrogen at room temperature for 6 h then filteredthrough celite and concentrated. The residue was purified by prep HPLC(pH 2, ACN/H₂O) to give the desired product as a white solid. LC-MScalculated for C₂₂H₂₃F₂N₄O₄ [M+H]⁺ m/z: 445.2; found 445.2. ¹H NMR (500MHz, DMSO) δ 11.93 (s, 1H), 8.04 (s, 1H), 7.54-7.47 (m, 1H), 7.03 (t,J=8.1 Hz, 1H), 6.86-6.81 (m, 1H), 4.83 (d, J=13.2 Hz, 1H), 4.63 (d,J=13.2 Hz, 1H), 4.61-4.55 (m, 1H), 4.54-4.47 (m, 1H), 3.90 (s, 3H), 3.87(s, 3H), 2.29-2.12 (m, 2H), 2.06-1.96 (m, 1H), 1.86-1.66 (m, 2H),1.56-1.44 (m, 1H).

Example 753-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 74: 8 mg, 0.02 mmol) in isopropyl alcohol (5 mL) and water(0.25 mL) was added pyridinium tribromide (29 mg, 0.09 mmol). Theresulting yellow solution was warmed up to 30° C. and stirred forovernight. The reaction mixture was cooled to room temperature then zinc(24 mg, 0.37 mmol) and acetic acid (0.2 mL, 4 mmol) were added. Themixture was stirred at room temperature for 2 h then filtered andconcentrated. The residue was dissolved in MeOH then purified by prepHPLC (pH 2, ACN/H₂O) to give the desired product as a white solid. LC-MScalculated for C₂₂H₂₃F₂N₄O₅ [M+H]⁺ m/z: 461.2; found 461.2.

Example 763-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 2,3-difluoroaniline replacing cyclopropylamine. LC-MScalculated for C₂₃H₁₇F₄N₄O₃ (M+H)⁺ m/z: 473.1; found: 473.0. ¹H NMR (300MHz, DMSO) δ 11.84 (s, 1H), 8.09 (s, 1H), 7.77-7.65 (m, 1H), 7.57-7.48(m, 1H), 7.45-7.35 (m, 1H), 7.23-7.17 (m, 1H), 7.07 (t, J=8.2 Hz, 1H),5.15-4.85 (m, 2H), 4.48-4.42 (m, 1H), 3.90 (s, 6H).

Example 773-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 75 with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 76) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₃H₁₇F₄N₄O₄ (M+H)⁺ m/z: 489.1; found: 489.0. ¹HNMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.96 (s, 1H), 7.66 (q, J=8.4 Hz,1H), 7.48 (t, J=7.2 Hz, 1H), 7.36 (q, J=7.2 Hz, 1H), 7.06 (t, J=8.1 Hz,1H), 4.95 (d, J=14.0 Hz, 1H), 4.77 (d, J=14.0 Hz, 1H), 3.89 (s, 6H),2.55 (d, J=21.7 Hz, 1H), 2.35 (d, J=21.7 Hz, 1H).

Example 783-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 2-pyridinemethanamine replacing cyclopropylamine. LC-MScalculated for C₂₃H₂₀F₂N₅O₃ (M+H)⁺ m/z: 452.2; found: 452.1. ¹H NMR (500MHz, DMSO) δ 11.65 (s, 1H), 8.54 (d, J=4.2 Hz, 1H), 8.01 (s, 1H), 7.71(td, J=7.7, 1.7 Hz, 1H), 7.27-7.20 (m, 2H), 7.17 (d, J=7.9 Hz, 1H), 7.04(t, J=8.1 Hz, 1H), 6.11-6.06 (m, 1H), 5.44 (s, 2H), 4.91 (s, 2H), 3.89(s, 6H).

Example 793-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 75 with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 78) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₃H₂₀F₂N₅O₄ (M+H)⁺ m/z: 468.1; found: 468.1.

Example 801-(4-chlorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:1-(4-chlorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with p-chloroaniline replacing cyclopropylamine. LC-MScalculated for C₂₃H₁₈ClF₂N₄O₃ (M+H)⁺ m/z: 471.1; found: 471.0.

Step 2:1-(4-chlorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 75 with1-(4-chlorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onereplacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₃H₁₈ClF₂N₄O₄ (M+H)⁺ m/z: 487.1; found: 487.1. ¹HNMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.93 (s, 1H), 7.60-7.54 (m, 2H),7.52-7.46 (m, 2H), 7.05 (t, J=8.2 Hz, 1H), 4.83 (s, 2H), 3.88 (s, 6H),2.36 (s, 2H).

Example 811-(5-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:1-(5-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 2-amino-5-chloropyridine replacing cyclopropylamine.LC-MS calculated for C₂₂H₁₇ClF₂N₅O₃ (M+H)⁺ m/z: 472.1; found: 472.0.

Step 2:1-(5-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 75 with1-(5-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onereplacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₂H₁₇ClF₂N₅O₄ (M+H)⁺ m/z: 488.1; found: 488.1.

Example 823-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those forExample 45 with 3-amino-benzonitrile replacing cyclopropylamine. LC-MScalculated for C₂₄H₁₈F₂N₅O₃ (M+H)⁺ m/z: 462.1; found: 462.1.

Example 833-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 3-pyridinamine replacing cyclopropylamine. LC-MScalculated for C₂₂H₁₈F₂N₅O₃ (M+H)⁺ m/z: 438.1; found: 438.1. ¹H NMR (400MHz, DMSO) δ 11.84 (s, 1H), 8.75-8.68 (m, 2H), 8.11 (s, 1H), 8.03-7.97(m, 1H), 7.67-7.60 (m, 1H), 7.19-7.13 (m, 1H), 7.07 (t, J=8.2 Hz, 1H),5.01 (s, 2H), 4.31-4.26 (m, 1H), 3.90 (s, 6H).

Example 841-(3-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 3-chloro-2-fluoroaniline replacing cyclopropylamine.LC-MS calculated for C₂₃H₁₇ClF₃N₄O₃ (M+H)⁺ m/z: 489.1; found: 489.0.

Example 853-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1-(4-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

A container having a mixture ofN-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(prepared as described in Example 62, step 2; 100 mg, 0.2 mmol),1-methyl-1H-pyrazol-4-amine (Astatech, Cat #CL4553: 31 mg, 0.32 mmol),cesium carbonate (380 mg, 1.2 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042mmol) and palladium acetate (9.4 mg, 0.042 mmol) in toluene (3 mL) wasevacuated then filled with nitrogen. The mixture was stirred at 150° C.for 1 hour then cooled to room temperature and diluted with ethylacetate, washed with water. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₂₇H₂₈F₂N₇O₃ (M+H)⁺ m/z: 536.2;found: 536.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from step 1 was dissolved in tetrahydrofuran (3 mL, 40mmol) and cooled to 0° C. then triphosgene (75 mg, 0.25 mmol) andtriethylamine (150 μL, 1.0 mmol) were added. The mixture was stirred atroom temperature for 1 hour then concentrated. The residue was purifiedby flash chromatography to give the desired product. LC-MS calculatedfor C₂₈H₂₆F₂N₇O₄ (M+H)⁺ m/z: 562.2; found: 562.2.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from Step 2 was dissolved in trifluoroacetic acid (2 mL, 20mmol) and the resulting solution stirred at 70° C. for 1 hour. Then itwas concentrated and the residue was purified by prep HPLC (pH 2,ACN/H₂O) to give the desired product as a white solid. LC-MS calculatedfor C₂₀H₁₈F₂N₇O₃ (M+H)⁺ m/z: 442.1; found: 442.1. ¹H NMR (500 MHz, DMSO)δ 8.30 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.07 (t, J=8.1 Hz, 1H), 6.26(s, 1H), 4.97 (s, 2H), 3.96 (s, 3H), 3.90 (s, 6H).

Example 863-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-pyridinemethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₂H₁₉F₂N₆O₃(M+H)⁺ m/z: 453.1; found: 453.1. ¹H NMR (500 MHz, DMSO) δ 8.61-8.55 (m,1H), 8.29 (s, 1H), 7.85 (td, J=7.8, 1.7 Hz, 1H), 7.78 (s, 1H), 7.39-7.31(m, 2H), 7.06 (t, J=8.1 Hz, 1H), 5.54 (s, 2H), 4.98 (s, 2H), 3.89 (s,6H).

Example 871-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with cyclopropylamine replacing 1-methyl-1H-pyrazol-4-aminein Step 1. LC-MS calculated for C₁₉H₁₈F₂N₅O₃ (M+H)⁺ m/z: 402.1; found:402.1. ¹H NMR (500 MHz, DMSO) δ 13.58 (br, 1H), 8.47 (s, 1H), 8.24 (s,1H), 7.04 (t, J=8.2 Hz, 1H), 4.70 (s, 2H), 3.88 (s, 6H), 3.38-3.29 (m,1H), 1.19-1.12 (m, 2H), 0.73-0.66 (m, 2H).

Example 883-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydro-2H-pyran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with (3S)-tetrahydro-2H-pyran-3-amine hydrochloride (J & WPharmLab, Cat #20-1041S) replacing 1-methyl-1H-pyrazol-4-amine inStep 1. LC-MS calculated for C₂₁H₂₂F₂N₅O₄ (M+H)⁺ m/z: 446.2; found:446.1.

Example 893-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydrofuran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with (3S)-tetrahydrofuran-3-amine hydrochloride (AdvancedChemBlocks, Cat #F4071) replacing 1-methyl-1H-pyrazol-4-amine in Step 1.LC-MS calculated for C₂₀H₂₀F₂N₅O₄ (M+H)⁺ m/z: 432.1; found: 432.2.

Example 903-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3R)-tetrahydrofuran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with (3R)-tetrahydrofuran-3-amine hydrochloride (AdvancedChemBlocks, Cat #F4072) replacing 1-methyl-1H-pyrazol-4-amine in Step 1.LC-MS calculated for C₂₀H₂₀F₂N₅O₄ (M+H)⁺ m/z: 432.1; found: 432.1.

Example 913-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isopropyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-propanamine replacing 1-methyl-1H-pyrazol-4-amine inStep 1. LC-MS calculated for C₁₉H₂₀F₂N₅O₃ (M+H)⁺ m/z: 404.2; found:404.1.

Example 923-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[2-(trifluoromethoxy)phenyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-(trifluoromethoxy)aniline replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₃H₁₇F₅N₅O₄(M+H)⁺ m/z: 522.1; found: 522.1.

Example 933-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those forExample 85 with 3-aminobenzonitrile replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₃H₁₇F₂N₆O₃(M+H)⁺ m/z: 463.1; found: 463.0.

Example 943-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 3-pyridinamine replacing 1-methyl-1H-pyrazol-4-amine inStep 1. LC-MS calculated for C₂₁H₁₇F₂N₆O₃ (M+H)⁺ m/z: 439.1; found:439.2. ¹H NMR (500 MHz, DMSO) δ 13.68 (s, 1H), 8.80 (dd, J=4.8, 1.4 Hz,1H), 8.76 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 8.08-8.03 (m, 1H), 7.71-7.66(m, 1H), 7.11-7.05 (m, 1H), 5.72 (s, 1H), 5.06 (s, 2H), 3.90 (s, 6H).

Example 953-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methyl-2H-tetrazol-5-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-methyl-2H-tetrazol-5-amine (Ark Pharm, Cat #AK-25219)replacing 1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated forC₁₈H₁₆F₂N₉O₃ (M+H)⁺ m/z: 444.1; found: 444.1. ¹H NMR (300 MHz, DMSO) δ13.84 (s, 1H), 8.39 (s, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.07 (s, 1H), 5.12(s, 2H), 4.59 (s, 3H), 3.91 (s, 6H).

Example 963-(2,6-difluoro-3,5-dimethoxyphenyl)-1-quinolin-8-yl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 8-quinolinamine replacing 1-methyl-1H-pyrazol-4-amine inStep 1. LC-MS calculated for C₂₅H₁₉F₂N₆O₃ (M+H)⁺ m/z: 489.1; found:489.2.

Example 971-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 52 with1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 87) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-onein Step 1. LC-MS calculated for C₂₀H₂₀F₂N₅O₃ (M+H)⁺ m/z: 416.2; found:416.1.

Example 983-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-9-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 52 with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 57) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-onein Step 1. LC-MS calculated for C₁₉H₂₀F₂N₅O₃ (M+H)⁺ m/z: 404.2; found:404.2. ¹H NMR (500 MHz, DMSO) δ 13.35 (s, 1H), 8.24 (s, 1H), 7.04 (t,J=8.1 Hz, 1H), 4.74 (s, 2H), 4.13 (q, J=6.9 Hz, 2H), 3.88 (s, 6H), 2.65(s, 3H), 1.21 (t, J=6.9 Hz, 3H).

Example 993-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 51, Step 1-2. LC-MS calculated for C₂₇H₂₆F₂N₅O₄ (M+H)⁺ m/z:522.2; found: 522.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(30.0 mg, 0.0575 mmol) in ethanol (1.0 mL, 17 mmol) andN-ethylethanamine (1.0 mL, 9.7 mmol) under nitrogen were added1,4-bis(diphenylphosphino)butane (7.6 mg, 0.017 mmol) andtris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.017 mmol). Theresulting mixture was heated to 90° C. and stirred for 6 h thenconcentrated. The residue was purified by column eluted with 1 to 10%MeOH in DCM to afford the desired product. LC-MS calculated forC₂₄H₂₂F₂N₅O₄ (M+H)⁺ m/z: 482.2; found: 482.2.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from step 2 was dissolved in TFA (1 mL) then heated to 75°C. and stirred for 1 h. The mixture was cooled to room temperature andconcentrated. The residue was purified by prep HPLC (pH 2,acetonitrile/water) to give the desired product. LC-MS calculated forC₁₆H₁₄F₂N₅O₃ (M+H)⁺ m/z: 362.1; found: 362.2.

Example 1003-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-[(Z)-2-ethoxyvinyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of2-[(Z)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (157 mg,0.792 mmol), 9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one(180.0 mg, 0.3963 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (48 mg, 0.059 mmol) and potassium carbonate(160 mg, 1.2 mmol) in 1,4-dioxane (3.0 mL)/water (1.0 mL) was heated at88° C. for 1.5 h. The mixture was cooled to room temperature thendiluted with water, extracted with DCM. The organic layer was washedwith brine then dried over Na₂SO₄ and concentrated. The residue waspurified via flash column to afford the desired product. LC-MScalculated for C₂₁H₂₂F₂N₅O₄ (M+H)⁺ m/z: 446.2; found: 446.1.

Step 2:[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-9-yl]acetaldehyde

The product from Step 2 was dissolved in acetone (2 mL) and ten drops ofconcentrated HCl was added. The resulting mixture was stirred at roomtemperature for 5 h then diluted with EtOAc and washed with saturatedNaHCO₃ and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was used in the next step without furtherpurification.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of the product from step 1 in MeOH was added morpholine (3eq.) and sodium cyanoborohydride (3 eq.). The resulting mixture wasstirred at room temperature for 1 h then purified by prep HPLC (pH 2,acetonitrile/water) to give the desired product. LC-MS calculated forC₂₃H₂₇F₂N₆O₄ (M+H)⁺ m/z: 489.2; found: 489.2. ¹H NMR (300 MHz, DMSO) δ13.67 (s, 1H), 8.25 (s, 1H), 7.04 (t, J=8.2 Hz, 1H), 4.81 (s, 2H),4.07-3.97 (m, 2H), 3.88 (s, 6H), 3.77-3.46 (m, 11H), 3.30-3.13 (m, 2H).

Example 1013-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclopropyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:2-chloro-N-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-6-fluoro-3,5-dimethoxyaniline

This compound was prepared using procedures analogous to those forExample 62, Step 2 with 2-chloro-6-fluoro-3,5-dimethoxyaniline replacing2,6-difluoro-3,5-dimethoxyaniline. LC-MS calculated for C₂₃H₂₂Cl₂FN₄O₃(M+H)⁺ m/z: 491.1; found: 491.1.

Step 2:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclopropyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with2-chloro-N-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-6-fluoro-3,5-dimethoxyanilinereplacingN-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyanilineand cyclopropylamine replacing 1-methyl-1H-pyrazol-4-aminedihydrochloride. LC-MS calculated for C₁₉H₁₈ClFN₅O₃ (M+H)⁺ m/z: 418.1;found: 418.0.

Example 1023-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 101 with cyclobutylamine replacing cyclopropylamine. LC-MScalculated for C₂₀H₂₀ClFN₅O₃ (M+H)⁺ m/z: 432.1; found: 432.1. ¹H NMR(500 MHz, DMSO) δ 13.63 (s, 1H), 8.29 (s, 2H), 7.01 (d, J=7.7 Hz, 1H),4.90-4.80 (m, 1H), 4.69 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.55-2.45(m, 2H), 2.40-2.30 (m, 2H), 1.88-1.71 (m, 2H).

Example 1033-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 44, Step 4: 52 mg, 0.095 mmol) and 1.0 M potassiumtert-butoxide in THF (1.0 mL, 1.0 mmol) was stirred at room temperaturefor 1 h. The mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄ and concentrated. The residue was dissolved in methanol and Pd/C(10%, 10 mg) was added and the reaction mixture was stirred underhydrogen balloon for 3 h. The mixture was filtered and the filtrate waspurified by prep-HPLC (pH 2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₁₇H₁₅F₂N₄O₃ (M+H)⁺ m/z: 361.1; found:361.1.

Example 1043-(2,6-difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: tert-butyl3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-iodo-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 33: 0.99 g, 2.6 mmol) in N,N-dimethylformamide (20 mL, 200mmol) was added potassium hydroxide (160 mg, 2.9 mmol). The mixture wasstirred at room temperature for 15 min then iodine (1.0 g, 4.0 mmol) wasadded. The resulting solution was stirred at room temperature for 1 hthen di-tert-butyldicarbonate (860 mg, 4.0 mmol) and4-dimethylaminopyridine (60 mg, 0.5 mmol) were added. The reactionmixture was stirred at room temperature for 1 h. The mixture was dilutedwith EtOAc then washed with water and brine. The organic layer was driedover Na₂SO₄ and concentrated. The residue was purified by column elutedwith 0 to 10% AcOEt in CH₂Cl₂. LC-MS calculated for C₂₃H₂₄F₂IN₄O₅ (M+H)⁺m/z: 601.1; found: 601.0.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of tert-butyl3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-iodo-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate(100.0 mg, 0.1666 mmol), 2.0 M dimethylzinc in toluene (0.17 mL, 0.33mmol), bis(tri-t-butylphosphine)palladium (5 mg, 0.01 mmol) intetrahydrofuran (5 mL, 60 mmol) was evacuated and filled with nitrogen.The reaction mixture was stirred at 65° C. for 2.5 h then cooled to roomtemperature and filtered. The filtrate was diluted with methanol andpurified with prep-HPLC (pH 2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₁₉H₁₉F₂N₄O₃ (M+H)⁺ m/z: 389.1; found:389.0. ¹H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 8.02 (s, 1H), 7.35 (s,1H), 7.02 (t, J=8.1 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 6H), 3.51 (s, 3H),2.42 (s, 3H).

Example 105[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile

Step 1:9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 33: 400 mg, 1.07 mmol) in N,N-dimethylformamide (10 mL) wasadded N-bromosuccinimide (210 mg, 1.2 mmol). The resulting red solutionwas stirred at room temperature for 2 h. The reaction was quenched withwater and extracted with DCM. The organic layer was washed with brinethen dried over Na₂SO₄ and concentrated. The residue was dissolved inDMF (5 mL) and cooled to 0° C., then NaH in mineral oil (60 wt %, 0.13g, 3.2 mmol) was added. The mixture was stirred at 0° C. for 30 min then[β-(trimethylsilyl)ethoxy]methyl chloride (0.36 g, 2.1 mmol) was added.The reaction mixture was stirred at room temperature for 2 h thendiluted with water and extracted with DCM. The organic layer was washedwith water, brine, then dried over Na₂SO₄ and concentrated. The residuewas purified by column eluted with 0 to 10% AcOEt in DCM to give thedesired product. LC-MS calculated for C₂₄H₃₀BrF₂N₄O₄Si (M+H)⁺ m/z:583.1; found: 583.0.

Step 2:[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile

To a mixture of9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(60 mg, 0.10 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.2 mg, 0.002mmol), tris(dibenzylideneacetone)dipalladium(0) (1.9 mg, 0.002 mmol), inN,N-dimethylformamide (2 mL) was added (trimethylsilyl)acetonitrile(17.6 μL, 0.128 mmol), followed by zinc difluoride (8.50 mg, 0.0823mmol). The mixture was evacuated then filled with nitrogen. The reactionmixture was stirred at 110° C. for overnight then cooled to roomtemperature and diluted with water. The mixture was extracted withEtOAc. The organic layer was washed with water, brine then dried overNa₂SO₄ and concentrated. The residue was dissolved in DCM (2 mL) and TFA(2 mL) was added. The resulting solution was stirred at room temperaturefor 1 h then concentrated. The residue was dissolved in MeOH thenethylenediamine was added. The mixture was stirred at room temperaturefor 1 h then purified by prep HPLC (pH 2, acetonitrile/water) to givethe desired product. LC-MS calculated for C₂₀H₁₈F₂N₅O₃ (M+H)⁺ m/z:414.1; found: 414.1.

Example 1063-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Step 1:4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.0g, 11 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride(60 wt % in mineral oil, 580 mg, 14 mmol) portion-wise at 0° C. Themixture was stirred at 0° C. for 30 min then[β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 13 mmol) was addeddropwise. The reaction mixture was stirred at 0° C. for 1.5 h thenquenched with saturated NH₄Cl solution. The mixture was then extractedwith EtOAc. The combined organic layer was washed with water, brine thendried over Na₂SO₄ and concentrated. The residue was purified by columneluted with 0 to 20% EtOAc in Hexanes to give the desired product (2.3g, 67%) as a white solid. LC-MS calculated for C₁₄H₂₀ClN₂O₂Si (M+H)⁺m/z: 311.1; found: 311.0.

Step 2:2-chloro-N-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-6-fluoro-3,5-dimethoxyaniline

To a solution of sodium triacetoxyborohydride (1.8 g, 8.8 mmol) intrifluoroacetic acid (4 mL) at 0° C. was added dropwise a solution of4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(600 mg, 1.9 mmol) and 2-chloro-6-fluoro-3,5-dimethoxyaniline (400.0 mg,1.945 mmol) in methylene chloride (10 mL). The reaction mixture wasstirred at 0° C. for 1 h then poured into ice-water and neutralized withNaHCO₃. The mixture was extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by column eluted with 0 to 5% AcOEt in CH₂Cl₂ to give thedesired product (0.6 g, 60%). LC-MS calculated for C₂₂H₂₉Cl₂FN₃O₃Si(M+H)⁺ m/z: 500.1; found: 500.0.

Step 3:5-{[(2-chloro-6-fluoro-3,5-dimethoxyphenyl)amino]methyl}-N-cyclobutyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of2-chloro-N-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-6-fluoro-3,5-dimethoxyaniline(0.10 g, 0.20 mmol), cyclobutylamine (34 μL, 0.40 mmol), palladiumacetate (4.5 mg, 0.020 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (10 mg, 0.02mmol), and cesium carbonate (2.0×10² mg, 0.60 mmol) in 1,4-dioxane (2mL, 20 mmol) was evacuated then filled with nitrogen. The mixture wasstirred at 160° C. for overnight. The reaction mixture was cooled toroom temperature then diluted with ethyl acetate (20 mL), filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluted with MeOH in DCM (0-5%) toafford the desired product. LC-MS calculated for C₂₆H₃₇ClFN₄O₃Si (M+H)⁺m/z: 535.2; found: 535.1.

Step 4:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of5-{[(2-chloro-6-fluoro-3,5-dimethoxyphenyl)amino]methyl}-N-cyclobutyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(82 mg, 0.15 mmol) in THF (5 mL) at 0° C. was added triethylamine (110μL, 0.76 mmol), followed by triphosgene (68 mg, 0.23 mmol). Theresulting mixture was stirred at 0° C. for 30 min then 1 N NaOH (2 mL)was added. The mixture was stirred at 0° C. for 10 min then diluted withwater and extracted with EtOAc. The organic layer was washed with brinethen dried over Na₂SO₄ and concentrated. The residue was used in thenext step without further purification. LC-MS calculated forC₂₇H₃₅ClFN₄O₄Si (M+H)⁺ m/z: 561.2; found: 561.1.

Step 5:3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

To a mixture of3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(82 mg, 0.15 mmol) in isopropyl alcohol (0.6 mL) and water (0.04 mL) wasadded pyridinium tribromide (180 mg, 0.51 mmol). The resulting solutionwas stirred at 30° C. for 2 h then cooled to room temperature and aceticacid (0.5 mL, 9 mmol) and zinc (95 mg, 1.5 mmol) were added. The mixturewas stirred at room temperature for 2 h then filtered and the filtratewas concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL)was added. The resulting solution was stirred at room temperature for 1h then concentrated. The residue was dissolved in MeOH (2 mL) thenethylenediamine (0.2 mL) was added. The mixture was stirred at roomtemperature for 1 h then purified by prep HPLC (pH 2,acetonitrile/water) to give the desired product. LC-MS calculated forC₂₁H₂₁ClFN₄O₄ (M+H)⁺ m/z: 447.1; found: 447.0.

Example 1073-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with 2-chloro-6-fluoro-3,5-dimethoxyaniline replacing2,6-difluoro-3,5-dimethoxyaniline in Step 1 and1-methyl-1H-pyrazol-4-amine dihydrochloride replacing cyclopropylaminein Step 3. LC-MS calculated for C₂₁H₁₉ClFN₆O₃ (M+H)⁺ m/z: 457.1; found:457.0.

Example 1083-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 107 with 3-pyridinamine replacing 1-methyl-1H-pyrazol-4-aminedihydrochloride. LC-MS calculated for C₂₂H₁₈ClFN₅O₃ (M+H)⁺ m/z: 454.1;found: 454.1.

Example 1093-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridazin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 45 with pyridazin-3-amine replacing cyclopropylamine in Step 3.LC-MS calculated for C₂₁H₁₇F₂N₆O₃ (M+H)⁺ m/z: 439.1; found: 439.2.

Example 1103-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(Example 70, Step 1: 1.09 g, 2.01 mmol) in methylene chloride (30 mL)was added morpholine (880 μL, 10. mmol), followed by acetic acid (1.0mL, 18 mmol). The resulting yellow solution was stirred at roomtemperature overnight, then sodium triacetoxyborohydride (1.3 g, 6.0mmol) was added. The mixture was stirred at room temperature for 4 h atwhich time LC-MS indicated the reaction completed to the desiredproduct. The reaction was quenched with saturated NaHCO₃ solution thenextracted with DCM. The organic extracts were combined then washed withwater and brine. The organic layer was dried over Na₂SO₄ thenconcentrated. The residue was purified by column eluted with 0 to 40%EtOAc/DCM to give the desired product as white solid (930 mg, 75%).LC-MS calculated for C₂₉H₃₀F₂N₅O₆S (M+H)⁺ m/z: 614.2; found: 614.0.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from Step 1 was dissolved in tetrahydrofuran (65 mL) then1.0 M tetra-n-butylammonium fluoride in THF (4.5 mL, 4.5 mmol) wasadded. The mixture was heated to 60° C. and stirred for 1.5 h at whichtime LC-MS indicated the reaction completed to the desired product. Themixture was cooled to room temperature then quenched with water andextracted with DCM. The combined extracts were combined then washed withwater and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by column eluted with 0 to 10%MeOH/DCM to give the desired product (649 mg, 68%) which was furtherpurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₃H₂₆F₂N₅O₄ (M+H)⁺ m/z: 474.2; found: 474.2. ¹H NMR (500 MHz, DMSO) δ11.75 (s, 1H), 8.04 (s, 1H), 7.03 (t, J=8.2 Hz, 1H), 6.95 (s, 1H), 4.77(s, 2H), 4.39 (s, 2H), 3.89 (s, 6H), 3.81 (br, 4H), 3.67 (s, 3H), 3.18(br, 4H).

Example 1113-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-hydroxypiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 70 with 4-hydroxypiperidine replacing 1-ethylpiperazine in Step2. LC-MS calculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺ m/z: 488.2; found: 488.1.

Example 1123-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4,4-difluoropiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 70 with 4,4-difluoropiperidine hydrochloride replacing1-ethylpiperazine in Step 2. LC-MS calculated for C₂₄H₂₆F₄N₅O₃ (M+H)⁺m/z: 508.2; found: 508.2.

Example 1133-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(3,3-difluoropiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 70 with 3,3-difluoropiperidine hydrochloride replacing1-ethylpiperazine in Step 2. LC-MS calculated for C₂₄H₂₆F₄N₅O₃ (M+H)⁺m/z: 508.2; found: 508.2.

Example 1143-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-morpholin-4-ylethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]acetaldehyde(Example 71, Step 2: 522 mg, 0.938 mmol) in methylene chloride (25 mL,390 mmol) was added morpholine (0.41 mL, 4.7 mmol), followed by aceticacid (0.32 mL, 5.6 mmol). The mixture was stirred at room temperaturefor 1 h then sodium triacetoxyborohydride (696 mg, 3.28 mmol) was added.The resulting mixture was stirred at room temperature for 1 h at whichtime LC-MS indicated the reaction completed to the desired product. Themixture was neutralized with saturated NaHCO₃ then extracted with DCM.The combined extracts were washed with brine then dried over Na₂SO₄ andconcentrated. The residue was purified by column eluted with 0 to 50%EtOAc/DCM then 0 to 10% MeOH/DCM to give the desired product (483 mg,82%) as a yellow solid. LC-MS calculated for C₃₀H₃₂F₂N₅O₆S (M+H)⁺ m/z:628.2; found: 628.0.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from Step 1 was dissolved in tetrahydrofuran (25 mL) then1.0 M potassium tert-butoxide in THF (2.3 mL, 2.3 mmol) was added. Theresulting mixture was stirred at room temperature for 30 min at whichtime LC-MS indicated the reaction completed to the desired product. Thereaction was quenched with saturated NH₄Cl solution then extracted withEtOAc. The combined extracts were washed with water and brine then driedover Na₂SO₄ and concentrated. The residue was purified by column elutedwith 0 to 10% MeOH/DCM, to give the desired product (258 mg, 56%) as awhite solid which was further purified by prep HPLC (pH=2,acetonitrile/water). LC-MS calculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺ m/z:488.2; found: 488.2. ¹H NMR (500 MHz, DMSO) δ 11.88 (s, 1H), 7.95 (s,1H), 7.04 (t, J=8.2 Hz, 1H), 6.67 (s, 1H), 4.75 (s, 2H), 4.06-3.95 (m,2H), 3.88 (s, 6H), 3.73-3.64 (m, 2H), 3.62 (s, 3H), 3.57-3.46 (m, 4H),3.22-3.09 (m, 4H).

Example 1158-(2-azetidin-1-ylethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 with azetidine hydrochloride replacing 1-ethylpiperazine inStep 3. LC-MS calculated for C₂₃H₂₆F₂N₅O₃ (M+H)⁺ m/z: 458.2; found:458.3.

Example 1163-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-pyrrolidin-1-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 with pyrrolidine replacing 1-ethylpiperazine in Step 3. LC-MScalculated for C₂₄H₂₈F₂N₅O₃ (M+H)⁺ m/z: 472.2; found: 472.3.

Example 1173-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(3-morpholin-4-ylpropyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 72 with morpholine replacing 1-ethylpiperazine in Step 4. LC-MScalculated for C₂₅H₃₀F₂N₅O₄ (M+H)⁺ m/z: 502.2; found: 502.2.

Example 1188-[3-(4-cyclopropylpiperazin-1-yl)propyl]-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 72 with 1-cyclopropylpiperazine dihydrochloride (Oakwood, Cat#029229) replacing 1-ethylpiperazine in Step 4. LC-MS calculated forC₂₈H₃₅F₂N₆O₃ (M+H)⁺ m/z: 541.3; found: 541.2.

Example 1193-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 40, Step 3 with 1-ethylpiperazine replacing 1-methylpiperazine.Purified by RP-HPLC (pH=2) to afford the desired product as a whitesolid. LC-MS calculated for C₂₅H₂₉F₂N₆O₄ [M+H]⁺ m/z: 515.2; found:515.2.

Example 1203-(2,6-difluoro-3,5-dimethoxyphenyl)-8-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]carbonyl}-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 40, Step 3 with cis-2,6-dimethylpiperazine (Aldrich, Cat#D179809) replacing 1-methylpiperazine. Purified by RP-HPLC (pH=2) toafford the desired product as a white solid. LC-MS calculated forC₂₅H₂₉F₂N₆O₄ [M+H]⁺ m/z: 515.2; found: 515.1.

Example 1213-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared as described in Example 49, Steps 1-3. LC-MScalculated for C₁₉H₁₉F₂N₄O₃ [M+H]⁺ m/z: 389.1; found: 389.1. ¹H NMR (500MHz, DMSO) δ 11.86 (s, 1H), 7.99 (s, 1H), 7.52-7.46 (m, 1H), 7.04 (t,J=8.2 Hz, 1H), 6.67-6.62 (m, 1H), 4.76 (s, 2H), 4.18 (q, J=6.9 Hz, 2H),3.89 (s, 6H), 1.34 (t, J=6.9 Hz, 3H).

Example 1224-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile

Step 1:4-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those forExample 45 with 4-aminobenzonitrile replacing cyclopropylamine. LC-MScalculated for C₂₄H₁₈F₂N₅O₃ (M+H)⁺ m/z: 462.1; found: 462.0.

Step 2:4-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those forExample 75 with4-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile(prepared in Step 1) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.LC-MS calculated for C₂₄H₁₈F₂N₅O₄ (M+H)⁺ m/z: 478.1; found: 478.0.

Example 1233-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]methyl}benzonitrile

Step 1:N-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

To a solution of sodium triacetoxyborohydride (6.2 g, 29 mmol) intrifluoroacetic acid (10.0 mL, 1.30E2 mmol) at 0° C. was added asolution of 2,6-difluoro-3,5-dimethoxyaniline (1.52 g, 8.03 mmol) inmethylene chloride (10 mL), followed by a solution of4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(Example 106, Step 1: 2.27 g, 7.30 mmol) in methylene chloride (40 mL,700 mmol). The reaction mixture was stirred at 0° C. for 1 h then pouredinto a cold aqueous solution of NaHCO₃ and then extracted with methylenechloride. The organic phase was washed with brine then dried over Na₂SO₄and concentrated. The residue was purified by flash chromatographyeluted with 0 to 40% EtOAc in DCM to give the desired product as ayellow oil which solidified on standing (3.32 g, 94%). LC-MS calculatedfor C₂₂H₂₉ClF₂N₃O₃Si (M+H)⁺ m/z: 484.2; found: 484.1.

Step 2:3-{[(5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]methyl}benzonitrile

A mixture ofN-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(110 mg, 0.23 mmol), 3-(aminomethyl)benzonitrile (45.0 mg, 0.341 mmol),palladium acetate (5.1 mg, 0.023 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (14 mg, 0.023 mmol),and cesium carbonate (220 mg, 0.68 mmol) in 1,4-dioxane (3 mL, 40 mmol)was evacuated then filled with nitrogen. The resulting mixture wasstirred at 150° C. for 2 h then cooled to room temperature and dilutedwith water and extracted with EtOAc. The organic layer was washed withwater, brine then dried over Na₂SO₄ and concentrated. The residue wasused in the next step without further purification. LC-MS calculated forC₃₀H₃₆F₂N₅O₃Si (M+H)⁺ m/z: 580.3; found: 580.2.

Step 3:3-[(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)methyl]benzonitrile

The crude product from step 2 was dissolved in tetrahydrofuran (5 mL, 60mmol) then triethylamine (0.16 mL, 1.1 mmol) was added, followed bytriphosgene (74 mg, 0.25 mmol). The resulting brown suspension wasstirred at room temperature for 30 min and then the reaction wasquenched with 3 mL of 1N NaOH solution. The mixture was stirred at roomtemperature for 20 min then extracted with EtOAc. The organic layer wasthen washed with water, brine and dried over Na₂SO₄ and concentrated.The residue was purified by column eluted with 0 to 50% EtOAc in hexanesto give the desired product. LC-MS calculated for C₃₁H₃₄F₂N₅O₄Si (M+H)⁺m/z: 606.2; found: 606.3.

Step 4:3-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]methyl}benzonitrile

To a solution of3-[(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)methyl]benzonitrile(60. mg, 0.099 mmol) in isopropyl alcohol (5 mL, 60 mmol) and water (0.5mL, 30 mmol) was added pyridinium tribromide (160 mg, 0.50 mmol). Theresulting yellow solution was stirred at 35° C. for 1 h then cooled toroom temperature and zinc (130 mg, 2.0 mmol) and acetic acid (0.11 mL,2.0 mmol) were added. The reaction mixture was stirred at roomtemperature for 2 h then filtered and washed with MeOH/DCM. The filtratewas concentrated and the residue was triturated with water and the whitesolid was collected via filtration then washed with water and dried.

The above solid was dissolved in 2 mL of DCM then 2 mL of TFA was added.The resulting yellow solution was stirred at room temperature 2 h thenconcentrated. The residue was dissolved in 5 mL of MeOH thenethylenediamine (0.33 mL, 5.0 mmol) was added. The resulting yellowsolution was stirred at room temperature for 2 h then purified by prepHPLC (pH 2, acetonitrile/water) to give the desired product as a whitesolid. LC-MS calculated for C₂₅H₂₀F₂N₅O₄ (M+H)⁺ m/z: 492.1; found:492.1.

Example 1243-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 106 with 2,3-difluoroaniline replacing cyclobutylamine in Step3. LC-MS calculated for C₂₃H₁₇ClF₃N₄O₄ (M+H)⁺ m/z: 505.1; found: 505.0.

Example 1254-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-3-fluorobenzonitrile

This compound was prepared using procedures analogous to those forExample 123 with 4-amino-3-fluorobenzonitrile replacing3-(aminomethyl)benzonitrile in Step 2. LC-MS calculated for C₂₄H₁₇F₃N₅O₄(M+H)⁺ m/z: 496.1; found: 496.0.

Example 1263-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 49, Step 3: 900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL)cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % inmineral oil). The resulting mixture was stirred at 0° C. for 30 min thenbenzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reactionmixture was stirred at 0° C. for 1.5 h at which time LC-MS showed thereaction completed to the desired product. The reaction was quenchedwith saturated NH₄Cl solution and diluted with water. The whiteprecipitate was collected via filtration then washed with water andhexanes, dried to afford the desired product (1.2 g, 98%) as a whitesolid which was used in the next step without further purification.LC-MS calculated for C₂₅H₂₃F₂N₄O₅S [M+H]⁺ m/z: 529.1; found: 529.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was addedfreshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF),3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. Thereaction mixture was stirred at −78° C. for 30 min then quenched withwater and extracted with EtOAc. The organic extracts were combined thenwashed with water and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography elutedwith 0 to 20% EtOAc in DCM to give the desired product as a white solid(1.68 g, 91%). LC-MS calculated for C₂₆H₂₃F₂N₄O₆S (M+H)⁺ m/z: 557.1;found: 556.9.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine(0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). Theresulting yellow solution was stirred at room temperature overnight thensodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture wasstirred at room temperature for 3 h at which time LC-MS showed thereaction went to completion to the desired product. The reaction wasquenched with saturated NaHCO₃ then extracted with ethyl acetate(EtOAc). The organic extracts were combined then washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography eluted with 0 to 40% EtOAcin DCM to give the desired product as a yellow solid (1.85 g, 95%).LC-MS calculated for C₃₀H₃₂F₂N₅O₆S (M+H)⁺ m/z: 628.2; found: 628.0.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was addedtetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). Theresulting solution was stirred at 50° C. for 1.5 h then cooled to roomtemperature and quenched with water. The mixture was extracted withdichloromethane (DCM) and the organic extracts were combined then washedwith water and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography elutedwith 0 to 10% MeOH in DCM to give the desired product as a white solid,which was further purified by prep HPLC (pH=2, acetonitrile/H₂O). LC-MScalculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺ m/z: 488.2; found: 488.0. ¹H NMR (500MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87(s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br,2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t,J=6.8 Hz, 3H).

Example 1273-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126 with 1-methylpiperazine replacing morpholine in Step 3. Theproduct was purified by prep HPLC (pH=2, acetonitrile/H₂O). LC-MScalculated for C₂₅H₃₁F₂N₆O₃ (M+H)⁺ m/z: 501.2; found: 501.1.

Example 1283-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126 with 1-ethylpiperazine replacing morpholine in Step 3. Theproduct was purified by prep HPLC (pH=2, acetonitrile/H₂O). LC-MScalculated for C₂₆H₃₃F₂N₆O₃ (M+H)⁺ m/z: 515.3; found: 515.1.

Example 1293-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126 starting with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(Example 70, Step 1) and 1-methylpiperazine. The product was purified byprep HPLC (pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₄H₂₉F₂N₆O₃(M+H)⁺ m/z: 487.2; found: 487.1.

Example 1303-(2,6-difluoro-3,5-dimethoxyphenyl)-8-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(Example 70, step 1: 500 mg, 0.9 mmol) in a mixture of tetrahydrofuran(25 mL), isopropyl alcohol (2.5 mL) and water (2.5 mL) was added 6.0 Mpotassium hydroxide in water (1.54 mL, 9.24 mmol). The resulting yellowsolution was stirred at room temperature overnight then warmed to 40° C.and stirred for 1 h. The reaction mixture was cooled to room temperatureand neutralized with 1 N HCl then saturated NH₄Cl solution was added.The resulting light yellow precipitate was collected via filtration anddried to give the product (350 mg, 90%) as a light yellow solid whichwas used in the next step without further purification. LC-MS calculatedfor C₁₉H₁₇F₂N₄O₄ (M+H)⁺ m/z: 403.1; found: 402.9.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(13 mg, 0.032 mmol) in methylene chloride (3 mL) was added1-piperazine-ethanol (20 μL, 0.16 mmol), followed by acetic acid (55 μL,0.97 mmol). The resulting yellow suspension was stirred at roomtemperature for 3 h then sodium triacetoxyborohydride (40. mg, 0.19mmol) was added. The mixture was stirred at room temperature overnight.The reaction was quenched with saturated NaHCO₃ solution then extractedwith methylene chloride. The organic extracts were combined then driedover Na₂SO₄ and concentrated. The residue was purified by prep HPLC(pH=2, acetonitrile/H₂O) to give the desired product as a white solid.LC-MS calculated for C₂₅H₃₁F₂N₆O₄ (M+H)⁺ m/z: 517.2; found: 517.1.

Example 1313-(4-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperazin-1-yl)propanenitrile

This compound was prepared using procedures analogous to those forExample 130 with 3-piperazin-1-ylpropanenitrile replacing1-piperazine-ethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₆H₃₀F₂N₇O₃ (M+H)⁺ m/z:526.2; found: 526.1.

Example 1321-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperidine-4-carbonitrile

This compound was prepared using procedures analogous to those forExample 130 with piperidine-4-carbonitrile replacing1-piperazine-ethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₅H₂₇F₂N₆O₃ (M+H)⁺ m/z:497.2; found: 496.9.

Example 133(3S)-1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}pyrrolidine-3-carbonitrile

This compound was prepared using procedures analogous to those forExample 130 with (3S)-pyrrolidine-3-carbonitrile hydrochloride replacing1-piperazineethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₄H₂₅F₂N₆O₃ (M+H)⁺ m/z:483.2; found: 483.2.

Example 1343-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(1-methylpiperidin-4-yl)amino]methyl}-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 130 with 1-methylpiperidin-4-amine replacing1-piperazine-ethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₅H₃₁F₂N₆O₃ (M+H)⁺ m/z:501.2; found: 501.0.

Example 1353-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(3S)-tetrahydrofuran-3-ylamino]methyl}-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 130 with (3S)-tetrahydrofuran-3-amine hydrochloride replacing1-piperazine-ethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₃H₂₆F₂N₅O₄ (M+H)⁺ m/z:474.2; found: 474.0.

Example 1363-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(3R)-tetrahydrofuran-3-ylamino]methyl}-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 130 with (3R)-tetrahydrofuran-3-amine hydrochloride replacing1-piperazine-ethanol in Step 2. The product was purified by prep HPLC(pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₃H₂₆F₂N₅O₄ (M+H)⁺ m/z:474.2; found: 474.2.

Example 1373-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1H-imidazol-1-ylmethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(hydroxymethyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(Example 70, step 1: 101 mg, 0.186 mmol) in tetrahydrofuran (5 mL)cooled to 0° C. was added sodium tetrahydroborate (21 mg, 0.56 mmol).The resulting mixture was stirred at 0° C. for 2 h and quenched withwater then extracted with EtOAc. The organic extracts were combined thenwashed with water and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₂₅H₂₃F₂N₄O₆S (M+H)⁺ m/z: 545.1;found: 545.0.

Step 2:8-(chloromethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from Step 1 was dissolved in methylene chloride (5 mL)and cooled to 0° C. then N,N-diisopropylethylamine (65 μL, 0.37 mmol)was added, followed by methanesulfonyl chloride (19 μL, 0.24 mmol). Theresulting mixture was warmed to room temperature and stirred overnight.The reaction was quenched with water then extracted with EtOAc. Theorganic extracts were combined then washed with water and brine. Theorganic layer was dried over Na₂SO₄ and concentrated. The residue wasused in the next step without further purification. LC-MS calculated forC₂₅H₂₂ClF₂N₄O₅S (M+H)⁺ m/z: 563.1; found: 562.9.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1H-imidazol-1-ylmethyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A mixture of8-(chloromethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(30. mg, 0.053 mmol), 1H-imidazole (18 mg, 0.27 mmol) and cesiumcarbonate (87 mg, 0.27 mmol) in acetonitrile (3 mL) was stirred at 60°C. for overnight at which time LC-MS indicated the reaction went tocompletion to the desired product. The mixture was cooled to roomtemperature and diluted with dichloromethane then washed with water andbrine. The organic layer was dried over Na₂SO₄ then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₈H₂₅F₂N₆O₅S (M+H)⁺ m/z: 595.2; found: 595.2.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1H-imidazol-1-ylmethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from Step 3 was dissolved in tetrahydrofuran (3 mL)then 1.0 M tetra-nbutylammonium fluoride in THF (0.27 mL, 0.27 mmol) wasadded. The mixture was stirred at 60° C. for 30 min at which time LC-MSindicated the reaction went to completion to the desired product. Thereaction mixture was cooled to room temperature then quenched with waterand extracted with dichloromethane. The organic extracts were combinedthen washed with water and brine. The organic layer was dried overNa₂SO₄ then concentrated. The residue was dissolved in MeOH thenpurified by prep HPLC (pH=2, acetonitrile/H₂O) to give the desiredproduct as a white solid. LC-MS calculated for C₂₂H₂₁F₂N₆O₃ (M+H)⁺ m/z:455.2; found: 455.1.

Example 1383-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(1H-pyrazol-1-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 137 with 1H-pyrazole replacing 1H-imidazole and the reactionmixture was stirred at 80° C. in Step 3. The product was purified byprep HPLC (pH=2, acetonitrile/H₂O). LC-MS calculated for C₂₂H₂₁F₂N₆O₃(M+H)⁺ m/z: 455.2; found: 454.9.

Example 1393-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[hydroxy(1-methyl-1H-pyrazol-4-yl)methyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(70.0 mg, 0.136 mmol) in tetrahydrofuran (2 mL) at −78° C. was addedfreshly prepared lithium diisopropylamide (0.5 M in THF, 0.3 mL, 0.15mmol). The resulting mixture was stirred at −78° C. for 30 min then asolution of 1-methyl-1H-pyrazole-4-carbaldehyde (45 mg, 0.41 mmol) inTHF (0.5 mL) was added. The reaction mixture was stirred at −78° C. for30 min then the reaction was quenched with water. The mixture was warmedto room temperature then extracted with EtOAc. The organic extracts werecombined then washed with water and brine. The organic layer was driedover Na₂SO₄ and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₉H₂₇F₂N₆O₆S (M+H)⁺m/z: 625.2; found: 624.9.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(1-methyl-1H-pyrazol-4-yl)methyl]-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A container having a mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[hydroxy(1-methyl-1H-pyrazol-4-yl)methyl]-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(crude product from Step 1: 50 mg, 0.08 mmol),2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (32mg, 0.080 mmol) and molybdenum hexacarbonyl (6 mg, 0.02 mmol) in1,4-dioxane (1 mL) was evacuated then filled with nitrogen. Theresulting mixture was stirred at 190° C. for 2 h then cooled to roomtemperature and quenched with water then extract with EtOAc. The organicextracts were combined then washed with water and brine. The organiclayer was dried over Na₂SO₄ then concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₂₉H₂₇F₂N₆O₅S (M+H)⁺ m/z: 609.2; found: 609.0.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from Step 2 was dissolved in THF (2 mL) then 1.0 Mpotassium tert-butoxide in THF (0.40 mL, 0.40 mmol) was added. Theresulting mixture was stirred at room temperature for 30 min thendiluted with MeOH and purified by prep-HPLC (pH=2, acetonitrile/H₂O).LC-MS calculated for C₂₃H₂₃F₂N₆O₃ (M+H)⁺ m/z: 469.2; found: 469.0.

Example 1403-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-pyridin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-8-[(E)-2-pyridin-2-ylvinyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

A container having a mixture of8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(40.0 mg, 0.0674 mmol), 2-vinylpyridine (21 mg, 0.20 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (3 mg, 0.004 mmol), and barium hydroxideoctahydrate (42 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL, 20 mmol)and a few drops of water was evacuated then filled with nitrogen. Theresulting mixture was stirred at 100° C. for 5 h then cooled to roomtemperature. The mixture was diluted with water then extracted withEtOAc. The organic extracts were combined then washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₃₁H₂₆F₂N₅O₅S (M+H)⁺ m/z: 618.2; found: 617.9.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(E)-2-pyridin-2-ylvinyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from Step 1 was dissolved in THF (2 mL) then 1.0 Mtetra-n-butylammonium fluoride in THF (674 μL, 0.674 mmol) was added.The resulting mixture was stirred at 60° C. for 2 h then cooled to roomtemperature and diluted with EtOAc. The mixture was washed with waterand brine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₅H₂₂F₂N₅O₃ (M+H)⁺ m/z: 478.2; found: 478.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-pyridin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The crude product from Step 2 was dissolved in MeOH (2 mL) thenPalladium (10 wt % on activated carbon, 30 mg) was added. The mixturewas stirred under a balloon of hydrogen at room temperature for 2 h thenfiltered and concentrated. The residue was dissolved in MeOH thenpurified by prep HPLC (pH=2, acetonitrile/H₂O). LC-MS calculated forC₂₅H₂₄F₂N₅O₃ (M+H)⁺ m/z: 480.2; found: 480.0.

Example 1413-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126 with3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 63, Step 5) replacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-onein Step 1. The product was purified by prep HPLC (pH=2,acetonitrile/H₂O). LC-MS calculated for C₂₄H₂₈ClFN₅O₄ (M+H)⁺ m/z: 504.2;found: 504.0.

Example 1428-[2-(diethylamino)ethyl]-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 with diethylamine replacing 1-ethylpiperazine in Step 3.LC-MS calculated for C₂₄H₃₀F₂N₅O₃ (M+H)⁺ m/z: 474.2; found: 474.0.

Example 1433-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 with 3-fluoroazetidine hydrochloride replacing1-ethylpiperazine in Step 3. LC-MS calculated for C₂₃H₂₅F₃N₅O₃ (M+H)⁺m/z: 476.2; found: 476.0.

Example 1443-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-methoxyazetidin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 with 3-methoxy-azetidine hydrochloride replacing1-ethylpiperazine in Step 3. LC-MS calculated for C₂₄H₂₈F₂N₅O₄ (M+H)⁺m/z: 488.2; found: 488.0.

Example 1453-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 101 with 1-methyl-1H-pyrazol-4-amine replacing cyclopropylamine.LC-MS calculated for C₂₀H₁₈ClFN₇O₃ (M+H)⁺ m/z: 458.1; found: 457.9. ¹HNMR (500 MHz, DMSO) δ 13.56 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.60(s, 1H), 7.04 (d, J=7.7 Hz, 1H), 6.23 (s, 1H), 4.91 (d, J=4.4 Hz, 2H),3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H).

Example 1463-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.08 g, 6.00 mmol)and cesium carbonate (3.91 g, 12.0 mmol) were dissolved inN,N-dimethylformamide (10 mL), light yellow suspension. The mixture wasstirred at room temperature for 20 min then benzenesulfonyl chloride(1.53 mL, 12.0 mmol) was added dropwise. After completion of theaddition, white-pinkish suspension was obtained. The mixture was stirredat room temperature for 2 h at which time LC-MS indicated the reactioncompleted to the desired product. The reaction mixture was diluted withwater. The solid was collected via filtration and washed with water thendried to give white solid (1.92 g, quant.), which was used in the nextstep without further purification. LC-MS calculated for C₁₄H₁₀ClN₂O₃S(M+H)⁺ m/z: 321.0; found: 320.9.

Step 2:N-{[4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

This compound was prepared using procedures analogous to those forExample 123, step 1 with4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehydereplacing4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde.LC-MS calculated for C₂₂H₁₉ClF₂N₃O₄S (M+H)⁺ m/z: 494.1; found: 494.1.

Step 3:N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1-(phenylsulfonyl)-1Hpyrrolo[2,3-b]pyridin-4-amine

A container having a mixture ofN-{[4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(480 mg, 0.97 mmol), 2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (337mg, 1.92 mmol), palladium acetate (22 mg, 0.097 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (56 mg, 0.097mmol), and cesium carbonate (630 mg, 1.94 mmol) in toluene (10 mL) wasdegassed then filled with nitrogen. The resulting mixture was stirred at120° C. for 2 h at which time LC-MS indicated the reaction completed tothe desired product. The mixture was cooled to room temperature thendiluted with DCM and filtered. The filtrate was concentrated and theresidue was purified by column eluted with 0 to 30% EtOAc/DCM to givethe desired product (625 mg, quant.). LC-MS calculated forC₃₀H₃₉F₂N₄O₅SSi (M+H)⁺ m/z: 633.2; found: 633.1.

Step 4:1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from Step 3 was dissolved in tetrahydrofuran (10 mL) thentriethylamine (0.70 mL, 5.0 mmol) was added, followed by triphosgene(290 mg, 0.97 mmol). The resulting suspension was stirred at roomtemperature for 30 min then the reaction was quenched with 10 mL of 1NNaOH solution. The mixture was stirred at room temperature for 2 h thenextracted with EtOAc. The combined extract was then washed with water,brine and dried over Na₂SO₄ and concentrated. The residue was purifiedby column eluted with 0 to 30% EtOAc/DCM to give the desired product(313 mg, 49%). LC-MS calculated for C₃₁H₃₇F₂N₄O₆SSi (M+H)⁺ m/z: 659.2;found: 659.2.

Step 5:8-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(313 mg, 0.475 mmol) in tetrahydrofuran (8 mL) at −78° C. was addedfreshly prepared lithium diisopropylamine solution (1M in THF, 0.5 mL,0.5 mmol). The mixture was stirred at −78° C. for 30 min, then asolution of 1,2-dibromo-1,1,2,2-tetrachloroethane (155 mg, 0.475 mmol)in 1 mL of THF was added. The mixture was stirred at −78° C. for 1 hthen quenched with saturated NH₄Cl solution. The mixture was warmed toroom temperature and extracted with EtOAc. The combined extract was thenwashed with water, brine then dried over Na₂SO₄ and concentrated. Theresidue was purified by column eluted with 0 to 20% EtOAc/DCM to givethe desired product (320 mg, 91%). LC-MS calculated forC₃₁H₃₆BrF₂N₄O₆SSi (M+H)⁺ m/z: 737.1; found: 736.9.

Step 6:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(2-morpholin-4-ylethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71, Step 1-3 starting with8-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from Step 5) and morpholine. LC-MS calculated for C₃₁H₃₄F₂N₅O₇S(M+H)⁺ m/z: 658.2; found: 658.2.

Step 7:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(2-morpholin-4-ylethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(16 mg, 0.024 mmol) in tetrahydrofuran (2 mL) was added 1.0 Mtetra-n-butylammonium fluoride in THF (120 μL, 0.12 mmol). The resultingyellow solution was stirred at 50° C. for 20 min at which time LC-MSindicated the reaction completed to the desired product. The mixture wascooled to room temperature then quenched with a few drops of TFA. Themixture was diluted with MeOH then purified by prep HPLC (pH=2,acetonitrile/water) to give the product as a white solid. LC-MScalculated for C₂₅H₃₀F₂N₅O₅ (M+H)⁺ m/z: 518.2; found: 518.0.

Example 1471-(3-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

This compound was prepared using procedures analogous to those forExample 123 with 3-chloropyridin-2-amine replacing3-(aminomethyl)benzonitrile in Step 2. LC-MS calculated forC₂₂H₁₇ClF₂N₅O₄ (M+H)⁺ m/z: 488.1; found: 488.1.

Example 1487′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′,7′-dihydrospiro[cyclobutane-1,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

This compound prepared using procedures analogous to those for Example66 with 1,3-dibromopropane replacing 1-bromo-2-chloroethane. The productwas purified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₁H₂₀F₂N₃O₃ (M+H)⁺ m/z: 400.1; found:400.0.

Example 1497′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′,7′-dihydrospiro[cyclopentane-1,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

This compound prepared using procedures analogous to those for Example66 with 1,4-dibromobutane replacing 1-bromo-2-chloroethane. The productwas purified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₂H₂₂F₂N₃O₃ (M+H)⁺ m/z: 414.2; found:414.1.

Example 1507′-(2,6-difluoro-3,5-dimethoxyphenyl)-2,3,5,6,6′,7′-hexahydrospiro[pyran-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

This compound prepared using procedures analogous to those for Example66 with bis(2-bromoethyl)ether replacing 1-bromo-2-chloroethane. Theproduct was purified by prep-HPLC (pH=2, acetonitrile/water) to give thedesired product. LC-MS calculated for C₂₂H₂₂F₂N₃O₄ (M+H)⁺ m/z: 430.2;found: 430.0.

Example 1517′-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

Step 1:tert-Butyl-7′-(2,6-difluoro-3,5-dimethoxyphenyl)-8′-oxo-3′-{[2-(trimethylsilyl)ethoxy]methyl}-3′,6′,7′,8′-tetrahydro-1H-spiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridine]-1-carboxylate

Nitrogen was bubbled through a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(Example 60, Step 2: 50.0 mg, 0.102 mmol) in DMF (1.1 mL) for 10 min andthen cesium carbonate (100.0 mg, 0.31 mmol) andtert-butyl-bis(2-chloroethyl)carbamate (0.0742 g, 0.306 mmol) were addedunder nitrogen and then the mixture was stirred at 50° C. for overnight.The mixture was filtered and then concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₃₃H₄₅F₂N₄O₆Si (M+H)⁺ m/z: 659.3; found: 659.4.

Step 2:7′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-{[2-(trimethylsilyl)ethoxy]methyl}-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

To a solution oftert-butyl-7′-(2,6-difluoro-3,5-dimethoxyphenyl)-8′-oxo-3′-{[2-(trimethylsilyl)ethoxy]methyl}-3′,6′,7′,8′-tetrahydro-1H-spiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridine]-1-carboxylate(95.5 mg, 0.145 mmol) (crude product from Step 1) in methylene chloride(0.5 mL) was added hydrogen chloride (4M in 1,4-dioxane, 0.5 mL, 2 mmol)and the mixture was stirred at room temperature for 45 min. Then thesolvent was removed under reduced pressure and the residue was used inthe next step without further purification. LC-MS calculated forC₂₈H₃₇F₂N₄O₄Si (M+H)⁺ m/z: 559.3; found: 559.3.

Step 3:7′-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3′-{[2-(trimethylsilyl)ethoxy]methyl}-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

A mixture of7′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-{[2-(trimethylsilyl)ethoxy]-methyl}-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one(20.0 mg, 0.0358 mmol) and formaldehyde (9.0 M in water, 12 μL, 0.11mmol) in methylene chloride (0.5 mL) was stirred at room temperature for5 min and then sodium triacetoxyborohydride (23 mg, 0.11 mmol) wasadded. The reaction mixture was stirred at room temperature for 30 minthen diluted with methylene chloride and washed with 1 N NaOH, water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to give the crude product which was used in the next stepwithout further purification. LC-MS calculated for C₂₉H₃₉F₂N₄O₄Si (M+H)⁺m/z: 573.3; found: 573.3.

Step 4:7′-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one

To a solution of7′-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3′-{[2-(trimethylsilyl)ethoxy]methyl}-6′,7′-dihydrospiro[piperidine-4,9′-pyrrolo[2,3-c][2,7]naphthyridin]-8′(3′H)-one(20.0 mg, 0.035 mmol) in methylene chloride (0.3 mL) was added TFA (0.2mL). The mixture was stirred at room temperature for 2 h thenconcentrated. The residue was dissolved in methanol (0.3 mL) and thenethylenediamine (0.2 mL) was added. The mixture was stirred at 50° C.for 1.5 h then cooled to room temperature and purified by prep-HPLC(pH=2, acetonitrile/water) to give the desired product. LC-MS calculatedfor C₂₃H₂₅F₂N₄O₃ (M+H)⁺ m/z: 443.2; found: 443.2.

Example 1527-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(morpholin-4-ylmethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Step 1: ethyl3-[[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate

A mixture ofN-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(Example 123, Step 1: 1.45 g, 3.00 mmol) and triethylamine (0.84 mL, 6.0mmol) in ethyl malonate (5.0 mL, 33 mmol) was stirred at 165° C. for 4 hthen cooled to room temperature. The mixture was concentrated underreduced pressure then purified by column eluted with 0 to 40%EtOAc/Hexanes to give the desired product (0.8 g, 44%). LC-MS calculatedfor C₂₇H₃₅ClF₂N₃O₆Si (M+H)⁺ m/z: 598.2; found: 598.0.

Step 2:7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of ethyl3-[[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate(1.60 g, 2.68 mmol) in toluene (10 mL) was added sodiumbis(trimethylsilyl)amide (589 mg, 3.21 mmol) and the mixture was stirredfor 15 min at room temperature under nitrogen. Thendibromobis(tri-t-butylphosphino)dipalladium (I) (Aldrich, cat #677728:62 mg, 0.080 mmol) was added and the mixture was evacuated then refilledwith nitrogen for three times. The reaction mixture was then stirred at115° C. for overnight. The mixture was cooled to room temperature thendiluted with methylene chloride, washed with saturated NaHCO₃, water andbrine. The organic layer was dried over Na₂SO₄ then concentrated. Theresidue was purified by column eluted with 0 to 40% EtOAc/Hexanes togive the desired product (0.81 g, 62%). LC-MS calculated forC₂₄H₃₀F₂N₃O₄Si (M+H)⁺ m/z: 490.2; found: 490.1.

Step 3:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Nitrogen was bubbled through a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(1.00 g, 2.04 mmol) in N,N-dimethylformamide (10 mL) for 20 min and thencesium carbonate (2.0 g, 6.1 mmol) and methyl iodide (509 μL, 8.17 mmol)were added under nitrogen. The resulting mixture was stirred at roomtemperature overnight. The mixture was filtered and then concentrated.The residue was purified by column eluted with 0 to 40% EtOAc/Hexanes togive the desired product (0.95 g, 90%). LC-MS calculated forC₂₆H₃₄F₂N₃O₄Si (M+H)⁺ m/z: 518.2; found: 518.2.

Step 4:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(1.0 g, 1.9 mmol) in methylene chloride (4 mL) was added trifluoroaceticacid (4 mL, 50 mmol). The mixture was stirred at room temperature for 2h then concentrated under reduced pressure. The residue was dissolved inmethanol (6 mL) and then ethylenediamine (3 mL) was added. The mixturewas stirred at 50° C. for 2.5 h then cooled to room temperature andconcentrated. The residue was triturated with water and the precipitatewas collected via filtration then washed with water and dried to givethe desired product (0.67 g, 90%). LC-MS calculated for C₂₀H₂₀F₂N₃O₃(M+H)⁺ m/z: 388.1; found: 388.2.

Step 5:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(0.070 g, 0.18 mmol) in dimethylformamide (DMF) (1.0 mL) was addedsodium hydride (0.0108 g, 0.271 mmol) (60% NaH dispersion in mineraloil) at 0° C. and the resulting mixture was stirred for 15 min. At thistime benzenesulfonyl chloride (25.4 μL, 0.199 mmol) was added and thereaction mixture was stirred for 1 h at 0° C. The reaction was quenchedby addition of saturated NH₄Cl aqueous solution then extracted withmethylene chloride. The combined extract was then washed with saturatedNaHCO₃, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluted with ethyl acetate in DCM(0 to 10%) to afford the desired product. LC-MS calculated forC₂₆H₂₄F₂N₃O₅S [M+H]⁺ m/z: 528.1; found 528.1.

Step 6:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridine-2-carbaldehyde

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(0.80 g, 1.5 mmol) in tetrahydrofuran (4 mL) at −78° C. was addedfreshly prepared lithium diisopropylamide (1M in THF, 2.3 mL, 2.3 mmol).The mixture was stirred for 0.5 h and then N,N-dimethylformamide (0.69mL, 8.9 mmol) was added. The mixture was stirred at −78° C. for 1 h thenquenched with water and warmed to room temperature. The mixture wasdiluted with methylene chloride, washed with saturated NaHCO₃, water andbrine. The organic layer was dried over Na₂SO₄, filtered and thenconcentrated. The mixture was used in the next step without furtherpurification. LC-MS calculated for C₂₇H₂₄F₂N₃O₆S (M+H)⁺ m/z: 556.1;found: 556.0.

Step 7:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(morpholin-4-ylmethyl)-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridine-2-carbaldehyde(0.50 g, 0.90 mmol) in 1,2-dichloroethane (12 mL) was added morpholine(0.47 mL, 5.4 mmol), followed by acetic acid (0.15 mL, 2.7 mmol). Themixture was stirred at room temperature overnight then sodiumtriacetoxyborohydride (570 mg, 2.7 mmol) was added and the reactionmixture was stirred at room temperature for 1 h. The mixture was dilutedwith methylene chloride, then washed with 1N NaOH, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column eluted with 0 to 20% EtOAc/DCM to givethe desired product (0.40 g, 71%). LC-MS calculated for C₃₁H₃₃F₂N₄O₆S[M+H]⁺ m/z: 627.2; found 627.3.

Step 8:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(morpholin-4-ylmethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a mixture of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(morpholin-4-ylmethyl)-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(0.48 g, 0.76 mmol) in tetrahydrofuran (8.0 mL) was added 1.0 Mtetra-n-butylammonium fluoride in THF (4.5 mL, 4.5 mmol). The reactionmixture was stirred at 60° C. for 1 h then cooled to room temperatureand quenched with water. The product was purified by prep-HPLC (pH=2,acetonitrile/water). LC-MS calculated for C₂₅H₂₉F₂N₄O₄ (M+H)⁺ m/z:487.2; found: 487.0. ¹H NMR (500 MHz, DMSO) δ 11.81 (s, 1H), 8.19 (s,1H), 7.06 (t, J=8.2 Hz, 1H), 6.91 (s, 1H), 4.91 (s, 2H), 4.40 (s, 2H),3.90 (s, 6H), 3.81 (s, 4H), 3.17 (s, 4H), 1.75 (s, 6H).

Example 1537-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Step 1:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 152, Step 7 with N-methyl piperazine replacing morpholine. LC-MScalculated for C₃₂H₃₆F₂N₅O₅S (M+H)⁺ m/z: 640.2; found: 640.3.

Step 2:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(25.0 mg) in THF (1.0 mL) was added 1 M TBAF in THF (0.1 mL). Themixture was stirred at 60° C. for 30 min then cooled to room temperatureand purified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₆H₃₂F₂N₅O₃ (M+H)⁺ m/z: 500.2; found:500.0.

Example 1547-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(4-ethylpiperazin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 153 with N-ethyl piperazine replacing N-methyl piperazine. LC-MScalculated for C₂₇H₃₄F₂N₅O₃ (M+H)⁺ m/z: 514.3; found: 514.0. ¹H NMR (500MHz, DMSO) δ 11.92 (s, 1H), 8.12 (s, 1H), 7.08 (t, J=8.2 Hz, 1H), 6.69(s, 1H), 4.90 (s, 2H), 3.94 (s, 2H), 3.90 (s, 6H), 3.51 (br, 2H),3.24-3.08 (m, 4H), 3.03 (br, 2H), 2.57 (br, 2H), 1.71 (s, 6H), 1.18 (t,J=7.3 Hz, 3H).

Example 1551-{[7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridin-2-yl]methyl}piperidine-4-carbonitrile

This compound was prepared using procedures analogous to those forExample 153 with piperidine-4-carbonitrile replacing N-methylpiperazine. LC-MS calculated for C₂₇H₃₀F₂N₅O₃ (M+H)⁺ m/z: 510.2; found:510.0.

Example 1567-(2,6-difluoro-3,5-dimethoxyphenyl)-2-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound prepared using procedures analogous to those for Example153 with (3S)-N,N-dimethylpyrrolidin-3-amine replacing N-methylpiperazine. LC-MS calculated for C₂₇H₃₄F₂N₅O₃ (M+H)⁺ m/z: 514.3; found:514.1.

Example 1577-(2,6-difluoro-3,5-dimethoxyphenyl)-2-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound prepared using procedures analogous to those for Example153 with (3R)-N,N-dimethylpyrrolidin-3-amine replacing N-methylpiperazine. LC-MS calculated for C₂₇H₃₄F₂N₅O₃ (M+H)⁺ m/z: 514.3; found:514.1.

Example 1587-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(2-morpholin-4-ylethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Step 1:2-bromo-7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(Example 152, Step 5: 0.25 g, 0.47 mmol) in tetrahydrofuran (5 mL) at−78° C. was added freshly prepared lithium diisopropylamide solution (1Min THF, 0.7 mL). The mixture was stirred at −78° C. for 30 min then asolution of 1,2-dibromo-1,1,2,2-tetrachloroethane (0.23 g, 0.71 mmol) inTHF (1 mL) was added. The resulting mixture was stirred at −78° C. for 1h then quenched with water and warmed to room temperature. The mixturewas extracted with EtOAc. The combined extract was washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column eluted with 0 to 10% EtOAc/DCM to givethe desired product. LC-MS calculated for C₂₆H₂₃BrF₂N₃O₅S (M+H)⁺ m/z:606.1; found: 605.8.

Step 2:7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(E)-2-ethoxyvinyl]-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a mixture of2-bromo-7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(0.10 g, 0.16 mmol),2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich,cat #731528: 0.033 g, 0.16 mmol) and sodium carbonate (0.035 g, 0.33mmol) in 1,4-dioxane (1 mL, 10 mmol)/water (0.2 mL, 10 mmol) was addeddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(3.5 mg, 0.0049 mmol). The mixture was evacuated then refilled with N₂for three times. The reaction mixture was then stirred at 95° C. forovernight then cooled to room temperature and diluted with DCM. Themixture was washed with water and brine. The organic layer was driedover Na2SO4 and concentrated. The residue was purified by column elutedwith 0 to 10% EtOAc/DCM to give the desired product. LC-MS calculatedfor C₃₀H₃₀F₂N₃O₆S (M+H)⁺ m/z: 598.2; found: 598.2.

Step 3:[7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridin-2-yl]acetaldehyde

The product from Step 2 was dissolved in tetrahydrofuran (1.0 mL) andthen concentrated HCl (0.1 mL) was added and the mixture was stirred atroom temperature for 2 h. The mixture was diluted with methylenechloride then washed with saturated NaHCO₃, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated to provide theproduct which was used in the next step without further purification.LC-MS calculated for C₂₈H₂₆F₂N₃O₆S (M+H)⁺ m/z: 570.1; found: 570.0.

Step 4:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

A mixture of[7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridin-2-yl]acetaldehyde(30.0 mg, 0.0527 mmol), morpholine (0.06 mL, 0.7 mmol) and acetic acid(0.030 mL) in methylene chloride (0.8 mL, 10 mmol) was stirred at roomtemperature for 1 h and then sodium triacetoxyborohydride (33 mg, 0.16mmol) was added. The reaction mixture was stirred at room temperatureovernight then diluted with methylene chloride, washed with saturatedNaHCO₃, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₃₂H₃₅F₂N₄O₆S (M+H)⁺ m/z:641.2; found: 641.0.

Step 5:7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(2-morpholin-4-ylethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

To a solution of7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one(25.0 mg) in THF (0.5 mL) was added 1 M potassium t-butoxide in THF (0.2mL). The mixture was stirred at room temperature for 30 min thenpurified by prep-HPLC (pH=2, acetonitrile/water) to give the desiredproduct. LC-MS calculated for C₂₆H₃₁F₂N₄O₄ (M+H)⁺ m/z: 501.2; found:501.0.

Example 1597-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[2-(4-ethylpiperazin-1-yl)ethyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 158 with N-ethyl piperazine replacing morpholine in Step 4.LC-MS calculated for C₂₈H₃₆F₂N₅O₃ (M+H)⁺ m/z: 528.3; found: 528.0.

Example 1607-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[2-(4-methylpiperazin-1-yl)ethyl]-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 158 with N-methyl piperazine replacing morpholine in Step 4.LC-MS calculated for C₂₇H₃₄F₂N₅O₃ (M+H)⁺ m/z: 514.3; found: 514.0.

Example 1613-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(1,3-oxazol-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(1,3-oxazol-4-yl)methanamine hydrochloride replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₀H₁₇F₂N₆O₄(M+H)⁺ m/z: 443.1; found: 443.1.

Example 1623-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(isoxazol-3-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-isoxazol-3-ylmethanamine hydrochloride replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₀H₁₇F₂N₆O₄(M+H)⁺ m/z: 443.1; found: 443.1.

Example 1633-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(1,3-thiazol-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(1,3-thiazol-4-yl)methanamine hydrochloride replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₀H₁₇F₂N₆O₃S(M+H)⁺ m/z: 459.1; found: 459.0.

Example 1643-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-[2-(difluoromethoxy)phenyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-(difluoromethoxy)aniline replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₃H₁₈F₄N₅O₄(M+H)⁺ m/z: 504.1; found: 503.9.

Example 1653-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-(1H-pyrazol-1-yl)ethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₁H₂₀F₂N₇O₃(M+H)⁺ m/z: 456.2; found: 456.0.

Example 1663-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-[(2R)-tetrahydrofuran-2-yl]methanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₁H₂₂F₂N₅O₄(M+H)⁺ m/z: 446.2; found: 445.9.

Example 1673-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-[(2S)-tetrahydrofuran-2-yl]methanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₁H₂₂F₂N₅O₄(M+H)⁺ m/z: 446.2; found: 446.0.

Example 1683-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-pyrazin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-pyrazin-2-ylethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=10, acetonitrile/water). LC-MS calculated for C₂₂H₂₀F₂N₇O₃(M+H)⁺ m/z: 468.2; found: 468.0.

Example 1693-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-pyridine-ethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₃H₂₁F₂N₆O₃(M+H)⁺ m/z: 467.2; found: 467.1.

Example 1703-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-3-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-pyridin-3-ylethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₃H₂₁F₂N₆O₃(M+H)⁺ m/z: 467.2; found: 467.1.

Example 1713-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 2-pyridin-4-ylethanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=10, acetonitrile/water). LC-MS calculated for C₂₃H₂₁F₂N₆O₃(M+H)⁺ m/z: 467.2; found: 467.0.

Example 1723-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-ethyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-ethyl-1H-pyrazol-4-amine (Ark Pharm, Cat #AK-43711)replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₁H₂₀F₂N₇O₃ (M+H)⁺ m/z: 456.2; found: 456.2.

Example 1733-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1H-pyrazol-4-amine

A mixture of 4-nitro-1H-pyrazole (0.50 g, 4.4 mmol),2,2-dimethyl-oxirane (1.1 mL, 13 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.8 mmol) in acetonitrile (5mL) was stirred at 70° C. for 1 hour. After cooling to room temperature,the mixture was diluted with water and extracted with EtOAc. Thecombined extracts were washed with water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in tetrahydrofuran (20 mL) then tert-butyldimethylsilylchloride (0.73 g, 4.9 mmol), 1H-imidazole (30 mg, 0.44 mmol) andtriethylamine (2.5 mL, 18 mmol) were added. The mixture was stirred atroom temperature overnight then diluted with water and extracted withEtOAc. The combined extracts were washed with water and brine. Theorganic layer was dried over Na₂SO₄ then filtered and concentrated. Theresidue was dissolved in methanol (30 mL) then palladium (10 wt % oncarbon, 110 mg, 0.10 mmol) was added. The suspension was stirred underH₂ atmosphere (balloon) at room temperature for overnight. The mixturewas filtered and the filtrate was concentrated to yield the desiredproduct, which was used in the next step without further purification.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1H-pyrazol-4-amine(product from step 1) replacing 1-methyl-1H-pyrazol-4-amine in Step 1.The product was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₃H₂₄F₂N₇O₄ (M+H)⁺ m/z: 500.2; found: 500.0.

Example 1743-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: 1-(2-methoxyethyl)-1H-pyrazol-4-amine

A mixture of 4-nitro-1H-pyrazole (0.5 g, 4 mmol), Ethane,1-bromo-2-methoxy (0.84 mL, 8.8 mmol), and potassium carbonate (1.2 g,8.8 mmol) in N,N-dimethylformamide (8 mL, 100 mmol) was stirred at 70°C. for 1 hour. After cooling to room temperature, the mixture wasdiluted with water then extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was dried over Na₂SO₄,filtered then concentrated. The residue was dissolved in methanol (10ml) then a catalytic amount of palladium (10 wt % on activated carbon)was added. The suspension was stirred under a balloon of H₂ at roomtemperature for 2 hours then filtered and concentrated. The residue wasused in the next step without further purification.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(2-methoxyethyl)-1H-pyrazol-4-amine (product fromstep 1) replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₂H₂₂F₂N₇O₄ (M+H)⁺ m/z: 486.2; found: 486.2.

Example 1753-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1: 1-(2,2-difluoroethyl)-1H-pyrazol-4-amine

A mixture of 4-nitro-1H-pyrazole (0.25 g, 2.2 mmol),1,1-difluoro-2-iodoethane (0.23 mL, 2.4 mmol), and potassium carbonate(0.61 g, 4.4 mmol) in acetonitrile (8 mL, 200 mmol) was stirred at 70°C. for 1 hour. After cooling to room temperature, the mixture wasdiluted with water then extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was dried over Na₂SO₄then concentrated. The residue was dissolved in methanol (8 mL) thenpalladium (10 wt % on activated carbon, 50 mg) was added. The suspensionwas stirred under H₂ atmosphere (balloon) at room temperature for 2hours then filtered and concentrated. The residue was used in the nextstep without further purification.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(2,2-difluoroethyl)-1H-pyrazol-4-amine (product fromstep 1) replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₁H₁₈F₄N₇O₃ (M+H)⁺ m/z: 492.1; found: 492.0.

Example 1763-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-methoxypyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(6-methoxypyridin-2-yl)methanamine (Ark Pharm, cat#AK-28243) replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₃H₂₁F₂N₆O₄ (M+H)⁺ m/z: 483.2; found: 483.0.

Example 1773-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(2-methoxypyridin-4-yl)methanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₃H₂₁F₂N₆O₄(M+H)⁺ m/z: 483.2; found: 483.0.

Example 1783-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3R)-tetrahydrofuran-3-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-[(3R)-tetrahydrofuran-3-yl]methanamine (AstaTech, cat#68889) replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₁H₂₂F₂N₅O₄ (M+H)⁺ m/z: 446.2; found: 446.0.

Example 1793-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydrofuran-3-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-[(3S)-tetrahydrofuran-3-yl]methanamine (AstaTech, cat#68891) replacing 1-methyl-1H-pyrazol-4-amine in Step 1. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₁H₂₂F₂N₅O₄ (M+H)⁺ m/z: 446.2; found: 446.0.

Example 1803-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 146, step 1-4 with 2-fluoro-benzenamine replacing2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine in Step 3. LC-MS calculatedfor C₂₉H₂₂F₃N₄O₅S (M+H)⁺ m/z: 595.1; found: 595.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126, step 2-4 starting with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from step 1). The product was purified by prep HPLC (pH=2,acetonitrile/water). LC-MS calculated for C₂₈H₂₇F₃N₅O₄ (M+H)⁺ m/z:554.2; found: 553.9.

Example 1813-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-(2-fluorophenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₃₀H₃₂F₃N₆O₃ (M+H)⁺ m/z: 581.2; found: 581.0.

Example 1821-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with cyclobutylamine replacing 2-fluorobenzenamine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₆H₃₀F₂N₅O₄ (M+H)⁺ m/z: 514.2; found: 514.0.

Example 1831-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 146 with cyclobutylamine replacing2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine in Step 3. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₇H₃₂F₂N₅O₄ (M+H)⁺ m/z: 528.2; found: 528.0.

Example 1843-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1-propyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 126, Step 1-3 starting with1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from Example 44, Step 2). LC-MS calculated for C₃₁H₃₂F₂N₅O₆S[M+H]⁺ m/z: 640.2; found 640.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1-propyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(20.0 mg, 0.0313 mmol) in methanol (1.0 mL) was added palladiumhydroxide (20 wt. % on carbon, 5.0 mg). The resulting mixture wasstirred under hydrogen atmosphere for 2 h before it was filtered andconcentrated in vacuo. The crude product was used directly in the nextstep without further purification. LC-MS calculated for C₃₁H₃₄F₂N₅O₆S[M+H]⁺ m/z: 642.2; found 642.2.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1-propyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was synthesized by the same method described in Example126, Step 4 by using3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1-propyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from Step 2) as starting material. LC-MS calculated forC₂₅H₃₀F₂N₅O₄ [M+H]⁺ m/z: 502.2; found 502.2.

Example 1853-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 39, step 5 starting with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from Example 126, step 1). LC-MS calculated for C₂₅H₂₂BrF₂N₄O₅S[M+H]⁺ m/z: 607.0; found 607.0.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 starting with8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from step 1) and morpholine. LC-MS calculated for C₂₅H₃₀F₂N₅O₄[M+H]⁺ m/z: 502.2; found 502.0. ¹H NMR (500 MHz, DMSO) δ 12.01 (s, 1H),7.97 (s, 1H), 7.04 (t, J=8.1 Hz, 1H), 6.55 (s, 1H), 4.75 (s, 2H), 4.16(q, J=6.8 Hz, 2H), 4.06-3.94 (m, 2H), 3.89 (s, 6H), 3.73-3.61 (m, 2H),3.58-3.43 (m, 4H), 3.25-3.07 (m, 4H), 1.34 (t, J=6.8 Hz, 3H).

Example 1861-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with cyclopropylamine replacing 2-fluorobenzenamine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₅H₂₈F₂N₅O₄ (M+H)⁺ m/z: 500.2; found: 500.0.

Example 1871-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 186 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₆H₃₁F₂N₆O₃ (M+H)⁺ m/z: 513.2; found: 513.0.

Example 1881-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 186 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₇H₃₃F₂N₆O₃ (M+H)⁺ m/z: 527.3; found: 527.1.

Example 1893-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with p-fluoroaniline replacing 2-fluorobenzenamine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₈H₂₇F₃N₅O₄ (M+H)⁺ m/z: 554.2; found: 554.0.

Example 1903-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 189 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₉H₃₀F₃N₆O₃ (M+H)⁺ m/z: 567.2; found: 567.0.

Example 1913-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 189 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₃₀H₃₂F₃N₆O₃ (M+H)⁺ m/z: 581.2; found: 581.1.

Example 1923-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 190 with 2,3-difluoroaniline replacing 4-fluoroaniline. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₉H₂₉F₄N₆O₃ (M+H)⁺ m/z: 585.2; found: 585.0.

Example 1933-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 192 with 1-ethylpiperazine replacing 1-methylpiperazine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₃₀H₃₁F₄N₆O₃ (M+H)⁺ m/z: 599.2; found: 599.0.

Example 1943-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1-pyridin-4-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with 4-pyridinamine replacing 2-fluorobenzenamine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₇H₂₇F₂N₆O₄ (M+H)⁺ m/z: 537.2; found: 537.0.

Example 1953-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1-pyridin-4-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 194 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₈H₃₀F₂N₇O₃ (M+H)⁺ m/z: 550.2; found: 550.1.

Example 1963-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(2-morpholin-4-ylethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 146, step 1-6 with 2-fluoro-benzenamine replacing2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine in step 3. LC-MS calculatedfor C₃₅H₃₃F₃N₅O₆S (M+H)⁺ m/z: 708.2; found: 708.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

The product from Step 1 was dissolved in tetrahydrofuran then potassiumtert-butoxide (1M in THF, 5 eq.) was added. The resulting mixture wasstirred at room temperature for 30 min then quenched with a few drops ofTFA and purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₉H₂₉F₃N₅O₄ (M+H)⁺ m/z: 568.2; found: 568.2.

Example 1973-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 196 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₃₀H₃₂F₃N₆O₃ (M+H)⁺ m/z: 581.2; found: 581.2.

Example 1983-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 196 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₃₁H₃₄F₃N₆O₃ (M+H)⁺ m/z: 595.3; found: 595.2.

Example 1993-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluoro-N-isopropylbenzamide

Step 1: methyl3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluorobenzoate

This compound was prepared using procedures analogous to those forExample 85 with methyl 3-amino-2-fluorobenzoate replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₄H₁₉F₃N₅O₅(M+H)⁺ m/z: 514.1; found: 514.0.

Step 2:3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluorobenzoicacid

The product from Step 1 was dissolved in tetrahydrofuran (10 mL) andwater (5 mL) then lithium hydroxide monohydrate (0.11 g, 2.5 mmol) wasadded. The reaction mixture was stirred at 50° C. overnight then cooledto room temperature and adjusted to pH=5 with aqueous 2N HCl. Themixture was extracted with EtOAc for three times. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to afford the desired product, whichwas used in the next step without further purification. LC-MS calculatedfor C₂₃H₁₇F₃N₅O₅ (M+H)⁺ m/z: 500.1; found: 499.9.

Step 3:3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluoro-N-isopropylbenzamide

To a mixture of3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluorobenzoicacid (8.9 mg, 0.018 mmol), 2-propanamine (1.6 mg, 0.027 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(8.7 mg, 0.020 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (9.3 μL, 0.054 mmol). The reaction mixture wasstirred at room temperature for 3 h and then purified by prep HPLC(pH=10, acetonitrile/water) to afford the desired product. LC-MScalculated for C₂₆H₂₄F₃N₆O₄ (M+H)⁺ m/z: 541.2; found: 541.0.

Example 200N-cyclopropyl-3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluorobenzamide

This compound was prepared using procedures analogous to those forExample 199 with cyclopropylamine replacing 2-propanamine in Step 3. Theproduct was purified by prep HPLC (pH=10, acetonitrile/water). LC-MScalculated for C₂₆H₂₂F₃N₆O₄ (M+H)⁺ m/z: 539.2; found: 539.0.

Example 2013-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-1-yl]-N-ethyl-2-fluorobenzamide

This compound was prepared using procedures analogous to those forExample 199 with ethylamine (2.0 M in THF) replacing 2-propanamine inStep 3. The product was purified by prep HPLC (pH=10,acetonitrile/water). LC-MS calculated for C₂₅H₂₂F₃N₆O₄ (M+H)⁺ m/z:527.2; found: 527.0.

Example 2023-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of1-allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(18.0 mg, 0.028 mmol, from Example 184, Step 1) in tetrahydrofuran (0.6mL) and dimethylamine (0.6 mL) were added1,4-bis(diphenylphosphino)butane (10.0 mg, 0.0227 mmol) andtris(dibenzylideneacetone)dipalladium(0) (10.0 mg, 0.0109 mmol). Thereaction was stirred at 90° C. overnight before it was concentrated invacuo and purified by column to afford the product. LC-MS calculated forC₂₈H₂₈F₂N₅O₆S [M+H]⁺ m/z: 600.2; found 600.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(10.0 mg, 0.0167 mmol, from Step 1), (2-methoxypyridin-4-yl)methanol(23.2 mg, 0.167 mmol, purchased from Ark Pharma, catalog number:AK-28607) in tetrahydrofuran (1.0 mL, 12 mmol) were addedtriphenylphosphine (26.0 mg, 0.0991 mmol) and diethyl azodicarboxylate(16 μL, 0.10 mmol). The resulting mixture was stirred at 60° C. for 12h. The reaction was diluted with MeOH (4.0 mL) and purified by RP-HPLC(pH 10) to afford the product. LC-MS calculated for C₃₅H₃₅F₂N₆O₇S [M+H]⁺m/z: 721.2; found 721.0.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methy]-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was synthesized by the same method described in Example126, Step 4 by using3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(product from Step 2) as starting material. LC-MS calculated forC₂₉H₃₁F₂N₆O₅ [M+H]⁺ m/z: 581.2; found 581.1.

Example 2033-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 180 with 1-methyl-1H-pyrazol-4-amine (Astatech Inc, catalog#CL4553) replacing 2-fluorobenzenamine. The product was purified by prepHPLC (pH=2, acetonitrile/water). LC-MS calculated for C₂₆H₂₈F₂N₇O₄(M+H)⁺ m/z: 540.2; found: 540.1.

Example 2043-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 203 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₇H₃₁F₂N₈O₃ (M+H)⁺ m/z: 553.2; found: 553.2.

Example 2053-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 203 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₂₈H₃₃F₂N₈O₃ (M+H)⁺ m/z: 567.3; found: 567.0.

Example 2067-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(3-hydroxyazetidin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 152 with azetidin-3-ol hydrochloride replacing morpholine inStep 7. LC-MS calculated for C₂₄H₂₇F₂N₄O₄ (M+H)⁺ m/z: 473.2; found:473.1.

Example 2077-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(3-fluoroazetidin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

This compound was prepared using procedures analogous to those forExample 152 with 3-fluoroazetidine hydrochloride replacing morpholine inStep 7. LC-MS calculated for C₂₄H₂₆F₃N₄O₃ (M+H)⁺ m/z: 475.2; found:475.0.

Example 2081-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}azetidine-3-carbonitrile

This compound was prepared using procedures analogous to those forExample 70 with azetidine-3-carbonitrile hydrochloride replacing1-ethylpiperazine in Step 2. LC-MS calculated for C₂₃H₂₃F₂N₆O₃ (M+H)⁺m/z: 469.2; found: 469.0.

Example 209(3R)-1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}pyrrolidine-3-carbonitrile

This compound was prepared using procedures analogous to those forExample 70 with (3R)-pyrrolidine-3-carbonitrile hydrochloride replacing1-ethylpiperazine in Step 2. LC-MS calculated for C₂₄H₂₅F₂N₆O₃ (M+H)⁺m/z: 483.2; found: 483.0.

Example 2103-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 146 with 3-fluoroazetidine hydrochloride replacing morpholine instep 6. The product was purified by prep HPLC (pH=2,acetonitrile/water). LC-MS calculated for C₂₄H₂₇F₃N₅O₄ (M+H)⁺ m/z:506.2; found: 506.0.

Example 2113-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 192 with morpholine replacing 1-methylpiperazine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₈H₂₆F₄N₅O₄ (M+H)⁺ m/z: 572.2; found: 571.9.

Example 2123-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared by using procedures analogous to those forExample 180 with 3-fluorobenzenamine replacing 2-fluorobenzenamine. Theproduct was purified by prep HPLC (pH=2, acetonitrile/water). LC-MScalculated for C₂₈H₂₇F₃N₅O₄ (M+H)⁺ m/z: 554.2; found: 554.2.

Example 2133-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 212 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₉H₃₀F₃N₆O₃ (M+H)⁺ m/z: 567.2; found: 567.2.

Example 2143-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 212 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₉H₃₀F₃N₆O₃ (M+H)⁺ m/z: 567.2; found: 567.2.

Example 2153-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 69 with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₂₁H₂₀F₂N₇O₃ (M+H)⁺ m/z: 456.2; found: 456.1.

Example 2163-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-fluoropyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(6-fluoropyridin-2-yl)methanamine hydrochloridereplacing 1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated forC₂₂H₁₈F₃N₆O₃ (M+H)⁺ m/z: 471.1; found: 471.0.

Example 2173-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-methylpyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 85 with 1-(6-methylpyridin-2-yl)methanamine replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₃H₂₁F₂N₆O₃(M+H)⁺ m/z: 467.2; found: 466.9.

Example 2183-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(3-fluoropyridin-2-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared by using procedures analogous to those forExample 85 with 3-fluoropyridin-2-amine replacing1-methyl-1H-pyrazol-4-amine in Step 1. LC-MS calculated for C₂₁H₁₆F₃N₆O₃(M+H)⁺ m/z: 457.1; found: 457.1.

Example 2193-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(2-oxopyridin-1(2H)-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(hydroxymethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(0.60 g, 1.1 mmol, from Example 126, Step 2) in methylene chloride (20mL) was added sodium triacetoxy-borohydride (0.80 g, 3.8 mmol). Themixture was stirred at room temperature for 3 h. The reaction mixturewas quenched with saturated aqueous NaHCO₃, and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withMeOH in DCM (0-5%) to afford the desired product (0.40 g, 66%). LC-MScalculated for C₂₆H₂₅F₂N₄O₆S (M+H)⁺ m/z: 559.1; found: 558.9.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(2-oxopyridin-1(2H)-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Triphenylphosphine (21 mg, 0.079 mmol) was added to a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(hydroxymethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(22 mg, 0.039 mmol) and 2-hydroxypyridine (7.4 mg, 0.078 mmol) intetrahydrofuran (0.5 mL) at room temperature. A solution of diethylazodicarboxylate (12 μL, 0.079 mmol) in tetrahydrofuran (0.3 mL) wasadded. The reaction mixture was stirred at room temperature overnight. Asolution of NaOMe in MeOH (25 wt %, 0.1 mL) was added. The reactionmixture was stirred at room temperature for 1 h. The mixture waspurified by RP-HPLC (pH=10) to afford the desired product. LC-MScalculated for C₂₅H₂₄F₂N₅O₄ (M+H)⁺ m/z: 496.2; found: 496.0.

Example 2203-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(pyridin-3-yloxy)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared by using procedures analogous to those forExample 219 with 3-pyridinol replacing 2-hydroxypyridine in Step 2.LC-MS calculated for C₂₅H₂₄F₂N₅O₄ (M+H)⁺ m/z: 496.2; found: 496.0.

Example 2213-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared by using procedures analogous to those forExample 126 (Step 2-4) with1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2Hpyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(from Example 146, Step 4) as starting material. LC-MS calculated forC₂₄H₂₈F₂N₅O₅ (M+H)⁺ m/z: 504.2; found: 504.0.

Example 2223-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 196, Steps 1-2 with 2,3-difluoroaniline replacing2-fluoro-benzenamine in Step 1. LC-MS calculated for C₂₉H₂₈F₄N₅O₄ (M+H)⁺m/z: 586.2; found: 586.0.

Example 2233-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 222 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₃₀H₃₁F₄N₆O₃ (M+H)⁺ m/z: 599.2; found: 599.0.

Example 2243-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 222 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₃₁H₃₃F₄N₆O₃ (M+H)⁺ m/z: 613.2; found: 613.0.

Example 2253-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 196, Steps 1-2 with 4-fluoro-benzenamine replacing2-fluoro-benzenamine in Step 1. LC-MS calculated for C₂₉H₂₉F₃N₅O₄ (M+H)⁺m/z: 568.2; found: 568.0.

Example 2263-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 225 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₃₀H₃₂F₃N₆O₃ (M+H)⁺ m/z: 581.2; found: 581.0.

Example 2273-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 196, Steps 1-2 with 3-fluoro-benzenamine replacing2-fluoro-benzenamine in step 1. LC-MS calculated for C₂₉H₂₉F₃N₅O₄ (M+H)⁺m/z: 568.2; found: 568.0.

Example 2283-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 227 with 1-methylpiperazine replacing morpholine. The productwas purified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculatedfor C₃₀H₃₂F₃N₆O₃ (M+H)⁺ m/z: 581.2; found: 581.0.

Example 2293-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 227 with 1-ethylpiperazine replacing morpholine. The product waspurified by prep HPLC (pH=2, acetonitrile/water). LC-MS calculated forC₃₁H₃₄F₃N₆O₃ (M+H)⁺ m/z: 595.3; found: 595.0.

Example 2301-{2-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-8-yl]ethyl}azetidine-3-carbonitrile

This compound was prepared using procedures analogous to those forExample 71 starting with8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 185, Step 1) and azetidine-3-carbonitrile hydrochloride. LC-MScalculated for C₂₅H₂₇F₂N₆O₃ [M+H]⁺ m/z: 497.2; found 496.9.

Example 2313-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 71 starting with8-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(Example 185, Step 1) and 3-fluoroazetidine hydrochloride. LC-MScalculated for C₂₄H₂₇F₃N₅O₃ [M+H]⁺ m/z: 490.2; found 489.9.

Example 2323-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

Step 1:1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(456 mg, 0.69 mmol) (Example 146, Step 4) in tetrahydrofuran (10 mL) at−78° C. was added LDA (freshly prepared, 1 M in THF, 1.44 mL). Themixture was stirred at −78° C. for 30 min, then N,N-dimethylformamide(0.77 mL) was added. The mixture was stirred at −78° C. for 1 h, andthen quenched with saturated NH₄Cl solution at −78° C. The mixture waswarmed to room temperature and extracted with EtOAc. The combinedextracts were washed with water and brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the desired product (452mg) as yellow solid, which was directly used in the next step withoutfurther purification. LC-MS calculated for C₃₂H₃₇F₂N₄O₇SSi [M+H]⁺ m/z:687.2; found 687.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

To a solution of1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(430 mg, 0.63 mmol) in tetrahydrofuran (10 mL) and water (2 mL) wasadded 12.0 M hydrogen chloride in water (1.04 mL). The resulting yellowsolution was stirred at room temperature for 1.5 h. The reaction mixturewas neutralized with saturated NaHCO₃ solution, and extracted withEtOAc. The combined extracts were washed with brine dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column eluting with EtOAc in DCM (gradient: 0 to60%) to afford the desired product (265 mg) as light yellow solid. LC-MScalculated for C₂₆H₂₃F₂N₄O₇S [M+H]⁺ m/z: 573.1; found 572.9.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 110, Step 1 starting with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehydeand morpholine. LC-MS calculated for C₃₀H₃₂F₂N₅O₇S [M+H]⁺ m/z: 644.2;found 644.0.

Step 4:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(from Step 3) was dissolved in DCM (3 mL). To the solution was addeddiethylaminosulfur trifluoride (40.0 μL, 0.303 mmol). The mixture wasstirred at r.t. for 2 h, quenched with water, and extracted with DCM.The organic layers were washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column with methanol in DCM (0-10%)to give the desired product. LC-MS calculated for C₃₀H₃₁F₃N₅O₆S [M+H]⁺m/z: 646.2; found 646.0.

Step 5:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one(from Step 4) was dissolved in THF (2.0 mL), then 1.0 M TBAF in THFsolution (0.40 mL) was added. The resulting solution was stirred at 60°C. for 1 h. After cooling, the solution was quenched with a few drops ofTFA, diluted with methanol, and purified by RP-HPLC (pH=2) to afford thedesired product as TFA salt. LC-MS calculated for C₂₄H₂₇F₃N₅O₄ [M+H]⁺m/z: 506.2; found 506.0.

Example 2333-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

This compound was prepared using procedures analogous to those forExample 232 starting with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde(Example 232, Step 2) and 1-methyl-piperazine replacing morpholine inStep 3. LC-MS calculated for C₂₅H₃₀F₃N₆O₃ [M+H]⁺ m/z: 519.2; found519.0.

Example A

FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was measured in anenzyme assay that measures peptide phosphorylation using FRETmeasurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.5 μL was transferred to the wells of a384-well plate. For FGFR3, a 10 μL volume of FGFR3 enzyme (Millipore)diluted in assay buffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 0.01%Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated for5-10 minutes. Appropriate controls (enzyme blank and enzyme with noinhibitor) were included on the plate. The assay was initiated by theaddition of a 10 μL solution containing biotinylated EQEDEPEGDYFEWLEpeptide substrate (SEQ ID NO: 1) and ATP (final concentrations of 500 nMand 140 μM respectively) in assay buffer to the wells. The plate wasincubated at 25° C. for 1 hr. The reactions were ended with the additionof 10 μL/well of quench solution (50 mM Tris, 150 mM NaCl, 0.5 mg/mLBSA, pH 7.8; 30 mM EDTA with Perkin Elmer Lance Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for ˜1 hr before scanning the wells on a PheraStar platereader (BMG Labtech).

FGFR1 and FGFR2 were measured under equivalent conditions with thefollowing changes in enzyme and ATP concentrations: FGFR1, 0.02 nM and210 μM, respectively and FGFR2, 0.01 nM and 100 μM, respectively. Theenzymes were purchased from Millipore or Invitrogen.

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.Y=Bottom+(Top−Bottom)/(1+10^((LogIC₅₀−X)*HillSlope)) where X is thelogarithm of concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

The compounds of the invention were found to be inhibitors of one ormore of FGFR1, FGFR2, and FGFR3 according to the above-described assay.IC₅₀ data is provided below in Table 1. The symbol “+” indicates an IC₅₀less than 100 nM and the symbol “++” indicates an IC₅₀ of 100 to 500 nM.

TABLE 1 FGFR1 FGFR2 FGFR3 Example No. IC50 (nM) IC50 (nM) IC50 (nM)1 + + + 2 + + + 3 + + + 4 + + + 5 + + + 6 + + + 7 + + + 8 + + + 9 + + ++10 + + + 11 + + + 12 + + + 13 + + + 14 + + + 15 + + + 16 + + + 17 + + +18 + + + 19 + + + 20 + + + 21 + + + 22 + + + 23 + + + 24 + + + 25 + + +26 + + + 27 + + + 28 + + + 29 + + + 30 + + + 31 + + + 32 + + + 33 + + +34 + + + 35 + + + 36 + + + 37 + + + 38 + + + 39 + + + 40 + + + 41 + + +42 + + + 43 + + + 44 + + + 45 + + + 46 + + + 47 + + + 48 + + + 49 + + +50 + + + 51 + + + 52 + + + 53 + + + 54 + + + 55 + + + 56 + + + 57 + + +58 + + + 59 + + + 60 + + + 61 + + + 62 ++ ++ + 63 + + + 64 + + +65 + + + 66 + + + 67 + + + 68 + + + 69 + + + 70 + + + 71 + + + 72 + + +73 + + + 74 + + + 75 + + + 76 + + + 77 + + + 78 + + + 79 + + + 80 + + +81 + + + 82 + + + 83 + + + 84 + + + 85 + + + 86 + + + 87 + + + 88 + + +89 + + + 90 + + + 91 + + + 92 + + + 93 + + + 94 + + + 95 + + + 96 + + +97 + + + 98 + + + 99 + + + 100 + + + 101 + + + 102 + + + 103 + + +104 + + + 105 + + + 106 + + + 107 + + + 108 + + + 109 + + + 110 + + +111 + + + 112 + + + 113 + + + 114 + + + 115 + + + 116 + + + 117 + + +118 + + + 119 + + + 120 + + + 121 + + + 122 + + + 123 + + + 124 + + +125 + + + 126 + + + 127 + + + 128 + + + 129 + + + 130 + + + 131 + + +132 + + + 133 + + + 134 + + + 135 + + + 136 + + + 137 + + + 138 + + +139 + + + 140 + + + 141 + + + 142 + + + 143 + + + 144 + + + 145 + + +146 + + + 147 + + + 148 + + + 149 + + + 150 + + + 151 + + + 152 + + +153 + + + 154 + + + 155 + + + 156 + + + 157 + + + 158 + + + 159 + + +160 + + + 161 + + + 162 + + + 163 + + + 164 + + + 165 + + + 166 + + +167 + + + 168 + + + 169 + + + 170 + + + 171 + + + 172 + + + 173 + + +174 + + + 175 + + + 176 + + + 177 + + + 178 + + + 179 + + + 180 + + +181 + + + 182 + + + 183 + + + 184 + + + 185 + + + 186 + + + 187 + + +188 + + + 189 + + + 190 + + + 191 + + + 192 + + + 193 + + + 194 + + +195 + + + 196 + + + 197 + + + 198 + + + 199 + + + 200 + + + 201 + + +202 + + + 203 + + + 204 + + + 205 + + + 206 + + + 207 + + + 208 + + +209 + + + 210 + + + 211 + + + 212 + + + 213 + + + 214 + + + 215 + + +216 + + + 217 + + + 218 + + + 219 + + + 220 + + + 221 + + + 222 + + +223 + + + 224 + + + 225 + + + 226 + + + 227 + + + 228 + + + 229 + + +230 + + + 231 + + + 232 + + + 233 + + +

Example B

FGFR Cell Proliferation/Survival Assays

The ability of the example compounds to inhibit the growth of cellsdependent on FGFR signaling for survival was measured using viabilityassays. A recombinant cell line over-expressing human FGFR3 wasdeveloped by stable transfection of the mouse pro-B Ba/F3 cells(obtained from the Deutsche Sammlung von Mikroorganismen andZellkulturen) with a plasmid encoding the full length human FGFR3. Cellswere sequentially selected for puromycin resistance and proliferation inthe presence of heparin and FGF 1. A single cell clone was isolated andcharacterized for functional expression of FGFR3. This Ba/F3-FGFR3 cloneis used in cell proliferation assays, and compounds are screened fortheir ability to inhibit cell proliferation/survival. The Ba/F3-FGFR3cells are seeded into 96 well, black cell culture plates at 3500cells/well in RPMI1640 media containing 2% FBS, 20 μg/mL Heparin and 5ng/mL FGF1. The cells were treated with 10 μL of 10× concentrations ofserially diluted compounds (diluted with medium lacking serum from 5 mMDSMO dots) to a final volume of 100 μL/well. After 72 hour incubation,100 μL of Cell Titer Glo® reagent (Promega Corporation) that measurescellular ATP levels is added to each well. After 20 minute incubationwith shaking, the luminescence is read on a plate reader. Theluminescent readings are converted to percent inhibition relative toDMSO treated control wells, and the IC₅₀ values are calculated usingGraphPad Prism software by fitting the data to the equation for asigmoidal dose-response with a variable slope. Compounds having an IC₅₀of 10 μM or less are considered active. Cell lines representing avariety of tumor types including KMS-11 (multiple myeloma, FGFR3translocation), RT112 (bladder cancer, FGFR3 overexpression), KatoIII(gastric cancer, FGFR2 gene amplification), and H-1581 (lung, FGFR1 geneamplification) are used in similar proliferation assays. In someexperiments, MTS reagent, Cell Titer 96® AQueous One Solution Reagent(Promega Corporation) is added to a final concentration of 333 μg/mL inplace Cell Titer Glo and read at 490/650 nm on a plate reader. Compoundshaving an IC₅₀ of 5 μM or less are considered active.

Example C

Cell-Based FGFR Phosphorylation Assays

The inhibitory effect of compounds on FGFR phosphorylation in relevantcell lines (Ba/F3-FGFR3, KMS-11, RT112, KatoIII, H-1581 cancer celllines and HUVEC cell line) can be assessed using immunoassays specificfor FGFR phosphorylation. Cells are starved in media with reduced serum(0.5%) and no FGF1 for 4 to 18 h depending upon the cell line thentreated with various concentrations of individual inhibitors for 1-4hours. For some cell lines, such as Ba/F3-FGFR3 and KMS-11, cells arestimulated with Heparin (20 μg/mL) and FGF1 (10 ng/mL) for 10 min. Wholecell protein extracts are prepared by incubation in lysis buffer withprotease and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl,1.5 mM MgCl₂, 10% Glycerol, 1% Triton X-100, 1 mM sodium orthovanadate,1 mM sodium fluoride, aprotinin (2 μg/mL), leupeptin (2 μg/mL),pepstatin A (2 μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4°C. Protein extracts are cleared of cellular debris by centrifugation at14,000×g for 10 minutes and quantified using the BCA (bicinchoninicacid) microplate assay reagent (Thermo Scientific).

Phosphorylation of FGFR receptor in protein extracts was determinedusing immunoassays including western blotting, enzyme-linked immunoassay(ELISA) or bead-based immunoassays (Luminex). For detection ofphosphorylated FGFR2, a commercial ELISA kit DuoSet IC Human Phospho-FGFR2α ELISA assay (R&D Systems, Minneapolis, Minn.) can be used. For theassay KatoIII cells are plated in 0.2% FBS supplemented Iscove's medium(50,000 cells/well/per 100 μL) into 96-well flat-bottom tissue culturetreated plates (Corning, Corning, N.Y.), in the presence or absence of aconcentration range of test compounds and incubated for 4 hours at 37°C., 5% CO₂. The assay is stopped with addition of 200 μL of cold PBS andcentrifugation. The washed cells are lysed in Cell Lysis Buffer (CellSignaling, #9803) with Protease Inhibitor (Calbiochem, #535140) and PMSF(Sigma, #P7626) for 30 min on wet ice. Cell lysates were frozen at −80°C. before testing an aliquot with the DuoSet IC Human Phospho-FGF R2αELISA assay kit. GraphPad prism3 was used to analyze the data. The IC₅₀values were derived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.

For detection of phosphorylated FGFR3, a bead based immunoassay wasdeveloped. An anti-human FGFR3 mouse mAb (R&D Systems, cat #MAB7661) wasconjugated to Luminex MAGplex microspheres, bead region 20 and used asthe capture antibody. RT-112 cells were seeded into multi-well tissueculture plates and cultured until 70% confluence. Cells were washed withPBS and starved in RPMI+0.5% FBS for 18 hr. The cells were treated with10 μL of 10× concentrations of serially diluted compounds for 1 hr at37° C., 5% CO₂ prior to stimulation with 10 ng/mL human FGF1 and 20μg/mL Heparin for 10 min. Cells were washed with cold PBS and lysed withCell Extraction Buffer (Invitrogen) and centrifuged. Clarifiedsupernatants were frozen at −80° C. until analysis.

For the assay, cell lysates are diluted 1:10 in Assay Diluent andincubated with capture antibody-bound beads in a 96-well filter platefor 2 hours at room temperature on a plate shaker. Plates are washedthree times using a vacuum manifold and incubated with anti-phospho-FGFR1-4 (Y653/Y654) rabbit polyclonal antibody (R&D Systems cat #AF3285)for 1 hour at RT with shaking Plates are washed three times. The dilutedreporter antibody, goat anti-rabbit-RPE conjugated antibody (InvitrogenCat. #LHB0002) is added and incubated for 30 minutes with shaking.Plates are washed three times. The beads are suspended in wash bufferwith shaking at room temperature for 5 minutes and then read on aLuminex 200 instrument set to count 50 events per sample, gate settings7500-13500. Data is expressed as mean fluorescence intensity (MFI). MFIfrom compound treated samples are divided by MFI values from DMSOcontrols to determine the percent inhibition, and the IC₅₀ values arecalculated using the GraphPad Prism software. Compounds having an IC₅₀of 1 μM or less are considered active.

Example D FGFR Cell-Based Signaling Assays

Activation of FGFR leads to phosphorylation of Erk proteins. Detectionof pErk is monitored using the Cellu'Erk HTRF (Homogeneous Time ResolvedFluororescence) Assay (CisBio) according to the manufacturer's protocol.KMS-11 cells are seeded into 96-well plates at 40,000 cells/well in RPMImedium with 0.25% FBS and starved for 2 days. The medium is aspiratedand cells are treated with 30 μL of 1× concentrations of seriallydiluted compounds (diluted with medium lacking serum from 5 mM DSMOdots) to a final volume of 30 μL/well and incubated for 45 min at roomtemperature. Cells are stimulated by addition of 10 μL of Heparin (100μg/mL) and FGF1 (50 ng/mL) to each well and incubated for 10 min at roomtemperature. After lysis, an aliquot of cell extract is transferred into384-well low volume plates, and 4 μL of detection reagents are addedfollowed by incubation for 3 hr at room temperature. The plates are readon a PheraStar instrument with settings for HTRF. The normalizedfluorescence readings are converted to percent inhibition relative toDMSO treated control wells, and the IC₅₀ values are calculated using theGraphPad Prism software. Compounds having an IC₅₀ of 1 μM or less areconsidered active.

Example E VEGFR2 Kinase Assay

40 μL Enzyme reactions are run in black 384 well polystyrene plates for1 hour at 25° C. Wells are dotted with 0.8 μL of test compound in DMSO.The assay buffer contains 50 mM Tris, pH 7.5, 0.01% Tween-20, 10 mMMgCl₂, 1 mM EGTA, 5 mM DTT, 0.5 μM Biotin-labeled EQEDEPEGDYFEWLEpeptide substrate (SEQ ID NO: 1), 1 mM ATP, and 0.1 nM enzyme (Milliporecatalogue number 14-630). Reactions are stopped by addition of 20 μLStop Buffer (50 mM Tris, pH=7.8, 150 mM NaCl, 0.5 mg/mL BSA, 45 mM EDTA)with 225 nM LANCE Streptavidin Surelight® APC (PerkinElmer cataloguenumber CR130-100) and 4.5 nM LANCE Eu-W1024 anti phosphotyrosine (PY20)antibody (PerkinElmer catalogue number AD0067). After 20 minutes ofincubation at room temperature, the plates are read on a PheraStar FSplate reader (BMG Labtech). IC₅₀ values can be calculated using GraphPadPrism by fitting the data to the equation for a sigmoidal dose-responsewith a variable slope. Compounds having an IC₅₀ of 1 μM or less areconsidered active.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound which is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one,or a pharmaceutically acceptable salt thereof.
 2. A compound which is3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one.3. A pharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient or carrier.
 4. A pharmaceuticalcomposition comprising the compound of claim 2 and at least onepharmaceutically acceptable excipient or carrier.